Although often considered in a negative light, cholesterol is an essential molecule with unusually diverse functions. Cholesterol and related sterols (ergosterol in yeast, phytosterols in plants) is considered a hallmark of eukaryotes, and may even have triggered the evolution of multicellular organisms. Synthesis of cholesterol is an extremely oxygen-intensive process and requires sufficient terrestrial oxygen to proceed. In turn, several lines of evidence support the argument that cholesterol evolved at least in part as an adaptation to the hazards of oxygen. This evolutionary perspective usefully informs medical research on cholesterol to address health-related issues, as illustrated by examples drawn from three prominent human diseases: cataracts, heart disease, and cancer.