Many 21st-century observers explain international efforts to control infectious diseases as a function of globalization and recent transformations in international commerce, transportation, and human migration. However, these contemporary global health initiatives can be more fully understood by also exploring the origins of international health organizations and regulations, which were initially dedicated exclusively to stemming the tide of infectious epidemics. This article reviews 3 eras of international approaches to controlling infectious diseases (1851-1881, 1881-1945, and 1945 to the present) and concludes by assessing how nations have a strong fiscal and humanitarian incentive to invest in infectious disease control programs and infrastructures in and beyond their own borders.