Osteoarthritis is the most common joint disorder and its prevalence is expected to climb as the age of the population increases. A hindrance to the development of disease-modifying drugs has been the inability to identify individuals who will rapidly progress towards severe disease. The principles of personalized medicine can be used to identify such individuals, which will enable the efficacy of disease-modifying drugs to be tested. Our current knowledge regarding the molecular pathogenesis of osteoarthritis indicates that there are several molecules that are candidates for therapeutic intervention and for which genetic variation affects disease risk and hence, they may be used in personalized medicine. Recent developments on the genetics of osteoarthritis from human association studies and animal models are discussed in this context.