This dissertation analyzes the fourteenth-century English and nineteenth-century Hopi experiences with the unwelcomed traveler of disease, specifically the Black Death and the smallpox outbreak of 1898-1899. By placing both peoples and events beside one another, it becomes possible to move past the death toll inflected by disease and see the role of diseases as a catalyst of historical change. Furthermore, this study places the Hopi experience with smallpox, and disease in general, in context with the human story of disease. The central methodical approach is ethnohistory, using firsthand accounts to reconstruct the cultural frameworks of the Hopi and the English. In analyzing the English and Hopi experiences this study uses the Medicine Way approach of three dimensions. Placing the first dimension approach (the English and the bubonic plague) alongside the third dimension approach (the Hopi and smallpox) demonstrates, not only the common ground of both approaches (second dimension), but the commonalities in the interactions of humans and disease. As my dissertation demonstrates, culture provides the framework, a system for living, for how individuals will interpret and react to events and experiences. This framework provides a means, a measure, to identify and strive for normalcy. There is a universal human drive to restore normalcy after one's world turns upside down, and in seeking to restore what was lost, society undergoes transformation. Disease creates opportunity for change and for balance to be restored. This study concludes disease is a catalyst of change because of how humans respond to it.