Joint surface defects (JSD) involving the articular cartilage and the subchondral bone are a common clinical problem in rheumatology and orthopaedics. The recent availability of accurate imaging for diagnosis and efficacious therapeutic options has stirred new interest in their natural history and biology. The evidence that some of these lesions can heal spontaneously whereas others precipitate osteoarthritis has raised important questions as to which lesions should be treated, when, and how. Evidence of repair of some of these lesions has also stimulated research into which factors contribute to successful healing and which ones determine chronic evolution and development of osteoarthritis (OA). Older anatomical observations, together with novel molecular tools and experimental models, have revealed a complex cellular and molecular response of cartilage to focal defects, which could explain differences in healing responses between individuals, and may provide clues to stimulating intrinsic tissue repair. In the first part of this review we will discuss clinical aspects of these lesions in the patient, with particular emphasis on their biology and natural history. In the second part we will summarize the data coming from in vitro and in vivo models of cartilage injury and regeneration, focussing on the molecular control of cartilage homeostasis after creation of cartilage surface defects.