Limb development requires the precise spatial and temporal regulation of the growth of skeletal elements. That many of the tissues of the growth region of a developing long bone interact with one another is almost self-evident from the fact that as the bone continuously grows, the tissues comprising its growth regions also grow and maintain their relative relationships with one another – and to the bone as a whole. One such interaction that we have studied involves the roles of the perichondrium (PC) and the periosteum (PO) in regulating growth of the underlying cartilage. The classic function attributed to the PC and PO is to contribute to the appositional growth of cartilage and bone by differentiating into chondrocytes and osteoblasts respectively. In addition, however, our results using an organ culture assay in which cartilage growth can be compared in intact tibias versus tibias from which the PC and PO have been removed, suggest that the PC and the PO also produce multiple, diffusible factors, that both positively and negatively regulate cartilage growth. Also, the negative regulators – of which there seem to be several – override the positive regulator(s). Importantly, this negative regulation is “precise” in that it results in cartilage growth that is the same as that effected by the endogenous PC and PO of the intact long bone. Another interaction we have found to occur in the growth region is the regulation by hypertrophic cartilage of the differentiation of the overlying preosteoblasts into osteoblasts. This regulation, we have determined, involves the production of transglutaminase by the hypertrophic chondrocytes. Taken together, these observations begin to unravel the multiple tissue interactions involved in the coordinated growth of a developing long bone. (This work was supported by the NIH.)