Osteoarthritis (OA) is an incurable, chronic, painful, debilitating joint disease characterized primarily by the gradual erosion of protective articular cartilage. Although joint damage contributes to the onset of OA, the continued synthesis of inflammatory cytokines, such as interleukin-1, by synovial cells and chondrocytes is thought to drive the progression of disease. Numerous naturally occurring proteins have been identified with the potential to block inflammatory processes, or alternatively, stimulate the repair of damaged cartilage. Problems lie in the lack of effective methods of delivery, as most proteins have limited half-lives in vivo. Through the use of gene therapy applications, exogenous transgenes can be delivered to cells and tissues of arthritic joints, thereby redirecting their biology for sustained, local synthesis of therapeutic transgene products. A wide variety of transgenes and methods of delivery are currently under investigation for their capacity to block ongoing inflammation or stimulate repair and regeneration of cartilage tissues in OA.