In anin vitromodel of granulation tissue, early passage human diploid fibroblasts under mechanical tension showed little or no apoptosis. Release of mechanical tension triggered an apoptotic response that occurred within 3–6 h and reached a plateau by 24 h. The percentage of apoptotic cells (∼15%) remained constant up to 7 days, and after 3 days, total cell number declined. Identification of mechanical unloading as a stimulus for apoptosis, without application of pharmacologic or genetic intervention, is a novel observation that permits us to model similar events that occur during wound healing. Studies on the mechanism regulating apoptosis under these conditions established that the apoptotic response does not require differentiation of cells into myofibroblasts but is governed by a combination of mechanical tension and growth factors in the collagen matrix.