One of the major drivers of change in the practice of cardiology, in both developed and developing countries, is population change, whose dynamics can be expressed by secular epidemiological and demographic trends, with increasing survival and life expectancy across all age strata. The sole concept of transition, whether epidemiological or demographic, is quite dynamic. From a global health point of view, one element merits attention: developed countries have had longer time to double or triple their population, usually more than one century, whereas the same increases in population size in the developing world occurred just over decades. The epidemiological transition theory, far from being perfect, introduced a booster to the understanding of the changing dynamics of epidemiological profiles and provided a complement to the discourse of the demographic change. In this article, with an special emphasis on the challenges faced by low- and middle-income settings, we describe current debates of the epidemiological 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 systems, prevention and treatment efforts; and physiological traits and human-environment interactions are identified. These challenges provide also an opportunity to redefine the agenda of global health cardiology and global cardiovascular research. This article concludes that a focus on the most populated regions of the world, who bear the highest disease burden related to cardiovascular conditions, will contribute substantially to protect the large gains in global survival and life expectancy accrued over the last decades. It then follows that a renewed workforce in global health cardiology must swiftly adapt to these changing environments. As the world changes, the practice of cardiology, clinical cardiology, global health cardiology and cardiology research will follow suit.