Osteoarthritis (OA) is the most common cause of arthritis and represents an enormous healthcare burden in industrialized societies. Current therapeutic approaches for OA are limited and are insufficient to prevent the initiation and progression of the disease. Genetic studies of patients with OA can help to unravel the molecular mechanisms responsible for specific disease manifestations, including joint damage, nociception and chronic pain. Indeed, these studies have identified molecules, such as growth/differentiation factor 5, involved in signaling cascades that are important for the pathology of joint components. Genome-wide association studies have uncovered a likely role in OA for the genes encoding structural extracellular matrix components (such as DVWA) and molecules involved in prostaglandin metabolism (such as DQB1 and BTNL2). A ∼300 kilobase region in chromosome 7q22 is also associated with OA susceptibility. Finally, the identification of individuals at a high risk of OA and of total joint arthroplasty failure might be facilitated by the use of combinations of genetic markers, allowing for the application of preventive and disease-management strategies.