Although the loss of good health is inherently unpredictable, human behavior at the individual and societal levels profoundly influences the incidence and evolution of disease. In this review, we define the human epidemiological environment and describe key biophysical, economic, sociocultural, and political factors that shape it. The potential impact upon the epidemiological environment of biophysical aspects of global change-changes in the size, mobility, and geographic distribution of the human population; land conversion; agricultural intensification; and climate change-is then examined. Human vulnerability to disease is strongly and deleteriously influenced by many of these ongoing, intensifying alterations. We then examine threats to human defenses against disease, including immune suppression, loss of biodiversity and indigenous knowledge, and the evolution of antibiotic resistance. Effective responses will require greatly enhanced attention by and collaboration among experts in diverse academic disciplines, in the private sector, and in government worldwide.