Biological regeneration is proving to be an increasingly attractive alternative/complement to prosthetic replacement of tissues and organs. In cell-based therapeutic approaches, cells are manipulated in vitro and administered to patients as living and dynamic biological agents. In this review, we have focused on the regeneration of the injured joint surface to discuss novel issues that these new therapeutic agents raise and are difficult to address within the paradigms of traditional pharmacology. They include: determination of the mechanism of action and dose, evaluation of potency, safety and toxicity, as well as upscale, delivery and identification of proper indications. Finally, novel potential approaches are proposed in which resident progenitor cells are targeted to regenerate the damaged tissue.