Mediation analysis is used to investigate how an independent variable, X, is related to an outcome variable, Y, through a mediator variable, M (MacKinnon, 2008). If X represents a randomized intervention it is difficult to make a cause and effect inference regarding indirect effects without making no unmeasured confounding assumptions using the potential outcomes framework (Holland, 1988; MacKinnon, 2008; Robins & Greenland, 1992; VanderWeele, 2015), using longitudinal data to determine the temporal order of M and Y (MacKinnon, 2008), or both. The goals of this dissertation were to (1) define all indirect and direct effects in a three-wave longitudinal mediation model using the causal mediation formula (Pearl, 2012), (2) analytically compare traditional estimators (ANCOVA, difference score, and residualized change score) to the potential outcomes-defined indirect effects, and (3) use a Monte Carlo simulation to compare the performance of regression and potential outcomes-based methods for estimating longitudinal indirect effects and apply the methods to an empirical dataset. The results of the causal mediation formula revealed the potential outcomes definitions of indirect effects are equivalent to the product of coefficient estimators in a three-wave longitudinal mediation model with linear and additive relations. It was demonstrated with analytical comparisons that the ANCOVA, difference score, and residualized change score models’ estimates of two time-specific indirect effects differ as a function of the respective mediator-outcome relations at each time point. The traditional model that performed the best in terms of the evaluation criteria in the Monte Carlo study was the ANCOVA model and the potential outcomes model that performed the best in terms of the evaluation criteria was sequential G-estimation. Implications and future directions are discussed.