Aging is a progressive and complicated bioprocess with overall decline in physiological function. Osteoarthritis (OA) is the most common joint disease in middle-aged and older populations. Since the prevalence of OA increases with age and breakdown of articular cartilage is its major hallmark, OA has long been thought of as “wear and tear” of joint cartilage. Nevertheless, recent studies have revealed that changes in the chondrocyte function and matrix components may reduce the material properties of articular cartilage and predispose the joint to OA. The aberrant gene expression in aging articular cartilage that is regulated by various epigenetic mechanisms plays an important role in age-related OA pathogenesis. This review begins with an introduction to the current understanding of epigenetic mechanisms, followed by mechanistic studies on the aging of joint tissues, epigenetic regulation of age-dependent gene expression in articular cartilage, and the significance of epigenetic mechanisms in OA pathogenesis. Our recent findings on age-dependent expression of 2 transcription factors, nuclear factor of activated T cell 1 (NFAT1) and SOX9, and their roles in the formation and aging of articular cartilage are summarized in the review. Chondrocyte dysfunction in aged mice, which is mediated by epigenetically regulated spontaneous reduction of NFAT1 expression in articular cartilage, is highlighted as an important advance in epigenetics and cartilage aging. Potential therapeutic strategies for age-related cartilage degeneration and OA using epigenetic molecular tools are discussed at the end.