Hypertrophy is a key component of endochondral ossification, the process controlling skeletal (cartilage, bone) development by differentiation of mesenchymal stem cells. Hypertrophic events also occur on cartilage injury such as during osteoarthritis (OA) and to a certain extent in focal lesions that may lead to OA if let untreated. Strategies based on the delivery on therapeutic genes and progenitor cells (the cells mostly recruited in spontaneous and guided repair) offer potential tools to delay or even prevent such undesirable events in sites of cartilage damage. The goal of this review is to revisit the mechanisms of hypertrophy during skeletal development and diseases and to provide an overview of the most recent advances in gene and stem cell therapy in the field of cartilage repair.