Osteoarthritis (OA) is the Western world's leading cause of disability. It is incurable, costly and responds poorly to treatment. This review discusses strategies for treating OA by gene therapy. As OA affects a limited number of weight-bearing joints and has no major extra-articular manifestations, it is well suited to local, intra-articular gene therapy. Possible intra-articular sites of gene transfer include the synovium and the cartilage. Most experimental progress has been made with gene transfer to synovium, a tissue amenable to genetic modification by a variety of vectors, using both in vivo and ex vivo protocols. The focus so far has been upon the transfer of genes whose products enhance synthesis of the cartilaginous matrix, or inhibit its breakdown, although there is certainly room for alternative targets. It is possible to build a convincing case implicating interleukin-1 (IL-1) as a key mediator of cartilage loss in OA, and the therapeutic effects of IL-1 receptor anatagonist (IL-1Ra) gene transfer have been confirmed in three different experimental models of OA. As transfer of IL-1Ra cDNA to human arthritic joints has already been accomplished safely, we argue that clinical studies of intra-articular IL-1Ra gene transfer in OA are indicated and should be funded. Of the available vector systems, recombinant adeno-associated virus may provide the best combination of safety with in vivo delivery using current technology.