Osteoarthritis (OA) is the most common degenerative disorder of the joints with an etiology involving genetic and environmental factors. Although various animal models have been used to elucidate the pathogenesis of OA, in the past decade gene targeting in mice has become one of the most powerful tools to dissect the molecular mechanisms of the disease. The generation of knockout mice has enormously accelerated the identification of the key genetic players in articular cartilage homeostasis and made a significant contribution to further our understanding of OA pathology. In this review, we will outline the phenotypes of the currently available mouse strains, carrying either engineered or spontaneous gene mutations, which provide insight into the processes of articular cartilage destruction. The analysis of these mice reveals a complex interaction among cytokines, proteases, transcription factors, extracellular matrix, cell surface and signaling molecules during the initiation and progression of OA and, in some cases, suggests new therapeutic interventions for the disease.