High-density lipoprotein (HDL) cholesterol has for decades been considered as the “good cholesterol” due to its inverse association with cardiovascular disease (CVD) risk in observational studies. However, human genetic studies have failed to establish a direct causal association between low HDL cholesterol concentrations and CVD. Moreover, the development of HDL cholesterol-increasing drugs has been pursued, yet their efficacy in reducing cardiovascular risk has been limited. Interestingly, recent studies now uncover unexpected relationships between high HDL cholesterol concentrations and several diseases. These studies, including 2 significant recent investigations, observe associations between high HDL cholesterol concentrations, all-cause mortality, cardiovascular mortality, and Alzheimer disease (1, 2). This perspective aims to summarize and discuss these emerging findings and their potential implications for our understanding of HDL cholesterol and for its use in clinical practice, focusing on the complex interplay between HDL cholesterol, disease risk, and underlying mechanisms.