Osteoarthritis is common, incurable and difficult to treat. Because osteoarthritis is symptomatic only in a limited number of weight-bearing joints and lacks obvious extra-articular manifestations, it is well suited to local therapy administered by intra-articular injection. Several biologically based, local therapies of this type are either in clinical use or in development. Intra-articular injections of hyaluronic acid are widely used, but are highly controversial because their mode of action is unclear and clinical trials have provided contradictory results. The conclusions of meta-analyses are also discordant. An alternative therapy, based on the intra-articular injection of autologous conditioned serum, is used in Europe. This product, known as Orthokine, is generated by incubating venous blood with etched glass beads. In this way, peripheral blood leukocytes produce elevated amounts of the interleukin-1 receptor antagonist and other anti-inflammatory mediators that are recovered in the serum. Considerable symptomatic relief has been reported in clinical trials of this product. Alternatively, instead of injecting a heterogeneous, incompletely characterized mixture of native molecules into the joint, it is possible to inject recombinant growth factors and cytokine antagonists. None of these are in routine clinical use, but promising preliminary human trials have been performed with insulin-like growth factor-1 and the interleukin-1 receptor antagonist. It is possible that sustained intra-articular production of such factors could be achieved by gene transfer. Although gene therapy for osteoarthritis is not yet a clinical reality, the first human trial should begin next year.