Osteoarthritis causes tremendous individual suffering and staggering societal costs, but due to our limited understanding of the underlying molecular and cellular mechanisms, our avenues for treating this disease are very restricted. Recent years have seen a drastic increase in the use of genetically modified mice to characterize the pathophysiology of osteoarthritis. Many new players and mechanisms driving osteoarthritis pathogenesis have been elucidated, some of which might be strong candidates as therapeutic targets for the human disease. The current review summarizes key findings (selected subjectively by the authors) from mouse osteoarthritis studies over recent years.