One of the major drivers of change in the practice of cardiology is population change. This article discusses the current debate about epidemiologic transition paired with other ongoing transitions with direct relevance to cardiovascular conditions. Challenges specific to patterns of risk factors over time; readiness for disease surveillance and meeting global targets; health system, prevention, and treatment efforts; and physiologic traits and human-environment interactions are identified. This article concludes that a focus on the most populated regions of the world will contribute substantially to protecting the large gains in global survival and life expectancy accrued over the last decades.