Osteoarthritis (OA) is a chronic arthropathy, in which cartilage loss, osteophyte formation, and subchondral bone sclerosis lead to pain, disability, and a reduction in quality of life. OA is a multifactorial disease and OA cases are affected by both genetics and environment to varying degrees. Strong familial aggregation and heritabilities have been reported for OA at the hip, knee, hand and spine. Candidate gene studies and genome-wide linkage studies have identified genes in the bone morphogenetic pathway (e.g. GDF5), the thyroid regulation pathway (DIO2), apoptotic pathways as involved in genetic risk of large joint OA. Genome wide association studies have reported structural genes (COL6A4/DVWA), inflammation related genes (PTGS2/PLA2G4A) and a locus on chr 7q22 associated with knee OA and a gene involved transcriptional regulation (A2BP1) to be associated with hand OA. During the coming years, as additional genetic and functional studies further define the genetic architecture of OA and the underlying molecular mechanisms, additional targets for novel therapies and improved diagnostic and prognostic tests will be identified.