Osteoarthritis (OA) is a progressive disease of cartilage degradation that significantly impacts quality of life. There are currently no effective treatments and, while a large number of potential therapeutic targets exist, most have not been validated in vivo. The range of OA models in the mouse has dramatically expanded in the last decade, beyond spontaneous models, to include genetically modified transgenic, knockout (KO) and knock-in (KI) mice that can develop premature cartilage degeneration reminiscent of OA. In addition, instability models of OA, either induced by intra-articular (IA) collagenase or surgery, are providing a set of tools to assist in the identification of disease-modifying OA drug (DMOAD) targets. These models are now vital tools to dissect the pathways essential to the pathogenesis of OA. Two targets, ADAMTS (a disintegrin and metalloproteinase with thrombospondin-like motifs)-5 and IL-1beta (interleukin-1 beta), have been validated in the surgical destabilization of the medial meniscus model (DMM) in KO mice. Other potential targets evaluated in instability models, either showed no disease modification or a worsening of disease, suggesting that those targets have no role, a protective role or that other, more destructive enzymes etc., can overcompensate. Development of small molecule or protein antagonist inhibitors of therapeutic targets require many years to bring to clinical trials and often confront potency and safety issues which impede successful progress. Validation, or confirmation of therapeutic targets in vivo is most clearly and efficiently obtained by using KO studies, than by creating potent and selective DMOADs to multiple potential targets. While the results in the mouse will not always transpose to the human condition, the track record of mouse knockouts corresponding to the human phenotype have been excellent. These results indicate that the evaluation of genetically modified mice will become increasingly important as we unravel the genes contributing to OA.