Osteoarthritis (OA) is the most common form of arthritis, yet has historically lagged far behind rheumatoid arthritis in terms of drug development. Despite the many challenges presented by clinical trials in OA, improvements in our understanding of disease pathogenesis and a move to treat pain, as well as underlying disease process, mean there are now many new pharmacological therapies currently in various stages of clinical trials. The medical need for these therapies and the evidence for recent tissue and molecular targets are reviewed. Current therapeutic examples in each area are discussed, including both novel therapeutics and existing agents which may be repurposed from other disease areas. Some challenges remain, but opportunities for improving symptoms and disease process in OA in the clinic with new pharmacological agents would appear to be on the close horizon.