The response of the heart to altered hemodynamic loading is growth or remodeling of myocytes and the extracellular matrix. In order to describe and mathematically model this dynamic and complex system of growing and resorbing tissue, the stimulating factor for tissue growth must be found, and up to now is not known. Most evidence, both in tissue and at the cellular level, points to a mechanical factor as the stimulus, and most likely a deformation signal is transduced to initiate protein synthesis. At the cellular level mechanotransduction likely takes place at the cellular membrane, although multiple biochemical and mechanical pathways have been proposed which induce transcription in the nucleus and eventual protein upregulation. The results of a recent mathematical analysis based on experimental data suggest that end-diastolic fiber strain at the tissue level may be the stimulus to one mode of tissue growth: volume-overload hypertrophy. This is the only mechanical factor that we found to be normalized after volume overload hypertrophy. But other studies do not agree with this result, and other modes of hypertrophy may be regulated by different factors or combinations of factors.