Osteoarthritis (OA) is considered a complex illness in which cross-talk between the different tissues of the joint plays a significant role in the evolution of the disease. Although we may not yet completely know all the initiating factors involved in the degeneration of the articular tissues, significant progress has been made with respect to the proposal of new concepts regarding the etiopathogenesis of this disease. For decades, the prevailing concept centered around the destruction of articular cartilage as the focal pathological feature of OA. Consequently, it is not surprising that investigators concentrated their efforts at identifying mechanisms involved in the destruction of this tissue. There is now substantial evidence, from preclinical and clinical studies, that changes in the subchondral bone metabolism comprise an integral component of the disease process, and its key role in the initiation and/or progression of cartilage degeneration may have been largely underestimated. This concept as well as the complex pathophysiological mechanisms taking place in this tissue during OA, are the focus of this chapter.