The angiotensin converting enzyme (ACE) I/D polymorphism has been one of the most studied genetic systems. It comprises hundreds of reports and a myriad of disease associations, including cardiovascular, metabolic, immune, cancer, aging, neurodegenerative and psychiatric diseases. Despite the wealth of information on the ACE polymorphism and the well-known functions of ACE, several questions arise. Why does the ACE polymorphism associate with so many diseases? What is its function? In this review, we summarize the current information on the ACE polymorphism and explain its function in the context of cell survival. We also provide a model to understand its role in biology and disease at the organism and population levels.