Cholesterol homeostasis plays a significant role in skeletal development and the dysregulation of cholesterol-related mechanism has been shown to be involved in the development of cartilage diseases including osteoarthritis (OA). Epidemiological studies have shown an association between elevated serum cholesterol levels and OA. Furthermore, abnormal lipid accumulation in chondrocytes as a result of abnormal regulation of cholesterol homeostasis has been demonstrated to be involved in the development of OA. Although, many in vivo and in vitro studies support the connection between cholesterol and cartilage degradation, the mechanisms underlying the complex interactions between lipid metabolism, especially HDL cholesterol metabolism, and OA remain unclear. The current review aims to address this problem and focuses on key molecular players of the HDL metabolism pathway and their role in ΟΑ pathogenesis. Understanding the complexity of biological processes implicated in OA pathogenesis, such as cholesterol metabolism, may lead to new targets for drug therapy of OA patients.