In the past decades, considerable efforts have been made to propose experimental and clinical treatments for articular cartilage defects. Yet, the problem of cartilage defects extending deep in the underlying subchondral bone has not received adequate attention. A profound understanding of the basic anatomic aspects of this particular site, together with the pathophysiology of diseases affecting the subchondral bone is the key to develop targeted and effective therapeutic strategies to treat osteochondral defects. The subchondral bone consists of the subchondral bone plate and the subarticular spongiosa. It is separated by the cement line from the calcified zone of the articular cartilage. A variable anatomy is characteristic for the subchondral region, reflected in differences in thickness, density, and composition of the subchondral bone plate, contour of the tidemark and cement line, and the number and types of channels penetrating into the calcified cartilage. This review aims at providing insights into the anatomy, morphology, and pathology of the subchondral bone. Individual diseases affecting the subchondral bone, such as traumatic osteochondral defects, osteochondritis dissecans, osteonecrosis, and osteoarthritis are also discussed. A better knowledge of the basic science of the subchondral region, together with additional investigations in animal models and patients may translate into improved therapies for articular cartilage defects that arise from or extend into the subchondral bone.