Osteoarthritis (OA) is a chronic disorder of the diarthrodial joints, mostly characterized by gradual deterioration of the articular cartilage. This disease still has no effective treatment. An emerging strategy for treating OA is based on molecular concepts using growth factors, transcription factors, and signaling molecules in light of their effects on the restoration of cartilage integrity. Recent studies have demonstrated that overexpression of such candidate molecules using direct gene transfer or ex vivo protocols is capable of stimulating cell proliferation and matrix synthesis in normal human and OA cartilage explants in vitro as well as in animal models in vivo. As a result, the structure of the articular cartilage can be improved. More insights into the pathophysiology of human OA and further studies in animal models are needed, however, to facilitate clinical translation of these molecular approaches. In conclusion, recent experimental findings permit cautious optimism, holding promise for treating human OA in the future.