The ability of tendon cells to sense and respond to load is central to the concept of mechanotransduction and the maintenance of tendon homeostasis. Tendon cells sense load through a mechano—electrochemical sensory system(s) that detects mechanical load signals through the deformation of the cellular membrane and/or the cytoskeleton. This cellular deformation produces tension in the cytoskeleton, which can be sensed by the cell nucleus through a mechano-sensory tensegrity system to elicit a metabolic response. While the precise level (magnitude, frequency/rate, and duration) of mechanobiological stimulation required to maintain normal tendon homeostasis is not currently known, it is very likely that an abnormal level(s) of stimulation may play a role in the etiopathogenesis of tendinopathy. Although tendinopathy has been well described pathologically, the precise etiopathogenesis of this condition remains unsettled. Classically, the etiology of tendinopathy has been linked to the performance of repetitive activities (so-called overuse injuries). This has led many investigators to suggest that it is the mechanobiologic over-stimulation of tendon cells from repetitive loading that is the initial stimulus for the degradative processes that have been shown to accompany tendinopathy. Although several studies have been able to demonstrate that the in vitro over-stimulation of tendon cells in monolayer can result in a pattern(s) of gene expression seen in clinical cases of tendinopathy the strain magnitudes and durations used in these in vitro studies, as well as the model systems, may not be clinically relevant. Using an in vitro rat tail tendon model, the objective of this research was to study the mechanobiologic response of tendon cells in situ (within their normal extracellular matrix), to various tensile loading regimes. The studies have shown that the gene response of tendon cells to load is both frequency and amplitude dependent and that tendon cells appear to be “programmed” to sense a certain level of stress. Model analyses combined with the experimental results have demonstrated that both strain rate and strain amplitude are able to independently alter rat interstitial collagenase gene expression through increases in fluid-flow-induced shear stress and matrix-induced cell deformation respectively. The studies have also shown that the absence of stress has a profound effect on the catabolic response of tendon cells, which in turn decreases the mechanical properties of the tendon independent of its collagen fiber distribution. The studies have shown that isolated fibrillar damage can occur within tendons and produce a localized upregulation of interstitial collagenase in response to altered (decreased) tendon cell stimulation. This weakens the tendon and may put more of the extracellular matrix at risk for further damage with subsequent loading. From these studies the hypothesis is forwarded that the etiopathogenic stimulus for the degenerative cascade that precedes the overt pathologic development of tendinopathy is the catabolic response of tendon cells to mechanobiologic under-stimulation as a result of microscopic damage to the collagen fibers of the tendon. This dissertation is a collection of research involving the response of tendon cells to changing load conditions and the examination of the implications of these responses as a potential etiopathogenic mechanism for the onset of tendinopathy.