In the last decade, huge steps forward have been made in the field of cartilage regeneration. The most recent trend for treating chondral/osteochondral lesions is based on the application of smart biomaterials that could lead to "in situ" regeneration of not only cartilage, but also subchondral bone, preferably through a single step procedure to reduce the costs and the morbidity for the patient. This innovative approach is currently under investigation as several "scaffolds" have been proposed in clinical practice, with or without the aid of cells, with the opportunity, in the second case, of bypassing the strict limits imposed by cell manipulation regulations. Furthermore, the fascinating potential of mesenchymal stem cells has recently opened new paths of research to discover how and whether these powerful entities can really contribute to tissue regeneration. The first clinical trials have been published but further high quality research is needed to understand their mechanisms of action, their limits, and their clinical efficacy.