Osteoarthritis (OA) is a degenerative joint disease particularly affecting the elderly population. Although several genetic features have been characterized as risk factors for OA susceptibility, a growing body of evidence indicates that epigenetic effectors may also modulate gene expression and thus contribute to OA pathology. One such epigenetic regulator of particular relevance to OA is Silent Information Regulator 2 type 1 (SirT1) which has been linked to aging and caloric intake, Consistently, SirT1 has been also connected with various age-associated diseases such as diabetes type II, Alzheimers and osteoporosis. Recent reports show that OA is linked to changes in SirT1 activity or levels within cartilage. In human chondrocytes, SirT1 plays a role in cartilage extracellular matrix (ECM) synthesis and promotes cell survival, even under proinflammatory stress. It appears that SirT1 fine tunes many cellular biochemical processes through its capacity to interact and modify various histone and non-histone proteins. Taken together these investigations demonstrate that SirT1 is involved in cartilage biology and could potentially serve as novel drug target in treating OA even at its premature stages, thereby possibly reversing mechanical-stress induced cartilage degeneration.