This chapter shows how sixteenth-century physicians built upon the broad conceptual and textual base provided by their classical and medieval predecessors, yet with a new focus on the role of poison to explain disease transmission in broad terms, not only the spread of pestilential disease. It shows how physicians endeavored to understand the complex relationships between poison, putrefaction, contagion, and disease. The chapter focuses on the numerous and varied physicians who most directly addressed the relationship between venenum and disease. It illustrates the contested nature of poison in the early sixteenth century by contrasting two particular points of view on the relationship between poison and contagion. The chapter focuses on Jean Fernel's strong argument that venenum served as the primary cause of virulent and contagious diseases. It explains how sixteenth-century discussions about the nature of disease and its transmission must be seen in light of the spread of Paracelsian ideas about the nature of poison and disease.