With the recent explosion of the elderly population, identification of factors involved in extended life with good health is particularly important for both individuals and societies. Epidemiological and interventional studies have demonstrated the importance of high-density lipoprotein cholesterol as a negative risk factor for cardiovascular disease. Also, certain genetic polymorphisms that are involved in high-density lipoprotein metabolism are proposed to be associated with longevity. These findings raise the possibility that enhancing high-density lipoprotein cholesterol levels by pharmacological intervention could prevent cardiovascular disease and promote healthy aging. The aim of this review is to summarize the current knowledge of high-density lipoprotein and its metabolism in relation with cardiovascular risk as well as frailty, a syndrome characterized by multisystem decline in the oldest old.