In the early 1960s, John W. Saunders Jr., Mary T. Gasseling, and Lilyan C. Saunders in the US investigated how cells die in the developing limbs of chick embryos. They studied when and where in developing limbs many cells die, and they studied the functions of cell death in wing development. At a time when only a few developmental biologists studied cell death, or apoptosis, Saunders and his colleagues showed that researchers could use embryological experiments to uncover the causal mechanisms of apotosis. The researchers published many of their results in the 1962 paper 'Cellular death in morphogenesis of the avian wing.'

This embryology image is a pencil sketch by Nicolaas Hartsoeker, published as part of his 1694 French-language paper entitled Essai de Dioptrique, a semi-speculative work describing the sorts of new scientific observations that could be done using magnifying lenses. Dioptrique was published in Paris by the publishing house of Jean Anisson. The image depicts a curled up infant-like human, now referred to as a homunculus, inside the head of a sperm cell. This sketch is important to embryology because it is one of the most illustrative examples of preformationism, a theory of generation stating that each future member of any given species exists, fully formed though miniscule, within the gametic cells (sperm or eggs) of its parents. This theory was popular among naturalists in the eighteenth century.

Nicolaas Hartsoeker, a Dutch astronomer, optics manufacturer, and naturalist, was born 26 March 1656 in Gouda, Netherlands, and died 10 December 1725. His mother was Anna van der Mey and his father was Christiaan Hartsoeker, a prominent evangelical minister. His major contribution to embryology was his observations of human sperm cells, which he claimed to be the first to see under a microscope. His sketch of the homunculus, a tiny preformed human he believed to exist in the head of spermatazoa, is his lasting scientific legacy in the field of embryology. This sketch was only a minor part of his first publication, Essai de Dioptrique (1694), which dealt primarily with the use of optical lenses in science. In subsequent years the sketch became iconic of the theory of embryological development known now as preformationism. Hartsoeker himself was a vocal adherent of spermist preformationism and is often cited as the originator of the idea.

Preformationism was a theory of embryological development used in the late seventeenth through the late eighteenth centuries. This theory held that the generation of offspring occurs as a result of an unfolding and growth of preformed parts. There were two competing models of preformationism: the ovism model, in which the location of these preformed parts prior to gestation was the maternal egg, and the spermism model, in which a preformed individual or homunculus was thought to exist in the head of each sperm. Preformationism was a widely-held theory by Enlightenment-era scientists, but by the early 1800s, most scientists had abandoned it, in part because higher magnification in microscopes enabled them to see the very earliest stages of embryos as small collections of cells. Prior to preformationism, naturalists who studied embryo development favored the theory of spontaneous generation in lower animals, such as flies, which appeared to arise from manure. In higher animals, however, scientists used the theory of epigenesis put forth by Aristotle, who said that maternal and paternal fluids came together in the uterus and solidified during early gestation into a fetus. Preformationism was the first theory of generation and development that applied to all organisms in the plant and animal kingdoms.

German embryologist Viktor Hamburger came to the US in 1932 with a fellowship provided by the Rockefeller Foundation. Hamburger started his research in Frank Rattray Lillie's laboratory at the University of Chicago. His two-year work on the development of the central nervous system (CNS) in chick embryos was crystallized in his 1934 paper, "The Effects of Wing Bud Extirpation on the Development of the Central Nervous System in Chick Embryos," published in The Journal of Experimental Zoology. Hamburger was able to use the microsurgical techniques that he had learned from Hans Spemann to show how wing buds influence the development of the CNS in chick embryos. This paper is one of several among Hamburger's important studies on chick embryos and represents the empirical and theoretical cornerstone for his further research on central-peripheral relations in the development of the nervous system.

An important question throughout the history of embryology is whether the formation of a biological structure is predetermined or shaped by its environment. If both intrinsic and environmental controls occur, how exactly do the two processes coordinate in crafting specific forms and functions? When Viktor Hamburger started his PhD study in embryology in the 1920s, few neuroembryologists were investigating how the central neurons innervate peripheral organs. As Hamburger began his research, he had no clue that central-peripheral relations in the development of the central nervous system (CNS) would become one of his major interests for the next seventy-five years. In fact, this research trajectory would lead him to discover programmed cell death as a pivotal mechanism mediating central-peripheral relations, as well as to Nobel-Prize-winning work on nerve growth factors (NGF).

The p53 protein acts as a pivotal suppressor of inappropriate cell proliferation. By initiating suppressive effects through induction of apoptosis, cell senescence, or transient cell-cycle arrest, p53 plays an important role in cancer suppression, developmental regulation, and aging. Its discovery in 1979 was a product of research into viral etiology and the immunology of cancer. The p53 protein was first identified in a study of the role of viruses in cancer through its ability to form a complex with viral tumor antigens. In the same year, an immunological study of cancer also found p53 due to its immunoreactivity with tumor antisera. Although a series of studies found p53 through various routes, and various researchers called it different names, it was eventually confirmed that they had all encountered the same protein, p53.

"Apoptosis: A Basic Biological Phenomenon with Wide-Ranging Implications in Tissue Kinetics" (hereafter abbreviated as "Apoptosis") was published in the British Journal of Cancer in 1972 and co-authored by three pathologists who collaborated at the University of Aberdeen, Scotland. In this paper the authors propose the term apoptosis for regulated cell death that proceeds through active, controlled morphological changes. This is in contrast to necrosis, a passive mode of cell death that results from uncontrolled cellular reactions to injury or stress. The journal article also suggests that apoptosis plays crucial roles in various pathological and physiological conditions including the shaping of digits and the shrinking of vestigial organs in developing embryos.

Richard A. Lockshin's 1963 PhD dissertation on cell death in insect metamorphosis was conducted under the supervision of Harvard insect physiologist Carroll M. Williams. Lockshin and Williams used this doctoral research as the basis for five articles, with the main title "Programmed Cell Death," that were published between 1964 and 1965 in the Journal of Insect Physiology. These articles examine the cytological processes, neuronal and endocrinal controls, and the influence of drugs on the mechanism of cell death observed in pupal muscle structures of the American silkmoth. Those muscle structures disappeared right after the completion of adult development. Several scientists have credited this series of articles as introducing the now standard term "programmed cell death." Among the five articles, "Endocrine Potentiation of the Breakdown of the Intersegmental Muscles of Silkmoths" (abbreviated hereafter as "Endocrine Potentiation") was published first and has been cited the most often. The article suggests that the endocrinal conditions at the beginning of the adult development are necessary, but not sufficient, for precisely scheduling three weeks later the cell death activities in the pupal intersegmental muscles of American silkmoths. The research was among the first to attempt to pinpoint the role of hormones in regulating cell death, a process integral to development.