Differentiation is the cellular process that regulates development of long bones and joint surface cartilage of synovial cavities. Growth plate cartilage development is commonly referred to as endochondral ossification which is the end stage of long bone development. Endochondral ossification proceeds as a continuum of chondrocyte proliferation cycles followed by non-proliferative phases coupled to extracellular matrix protein transformations that are regulated by proteins of the hedgehog family and by parathyroid-hormone-related peptide and its receptor, the parathyroid-hormone-related peptide receptor. A compelling body of evidence has now emerged implicating matrix metalloproteinases (MMPs) in the process of long bone lengthening and endochondral ossification. Among the MMPs, MMP-13 (collagenase-3), MMP-9 (92-kDa gelatinase; gelatinase B) and MMP-14 (MT1-MMP) are the most abundant proteinases that regulate cellular migration, alterations in the extracellular matrix and apoptosis in growth plate cartilage. Murine mutation or ablation models of growth plate development that target MMPs often result in skeletal abnormalities, indicating the critical role that MMPs play in these animal models and in skeletal maturation. Many of the MMPs that have been identified as regulating the spatial and temporal changes in rodent and rabbit endochondral ossification have also been identified by in situ hybridization and immunohistochemical analysis of human long bone development. Genetic manipulation to correct defective or dysfunctional MMP genes or MMP activity found in certain human chondrodysplasias may provide a novel strategy for treating medical disorders characterized by skeletal anomalies.