The cellular mechanisms of cardiac hypertrophy remain unclear despite tantalizing clues gleaned from a variety of experimental approaches. Here we examine the hypothesis that an increase in cytosolic free Ca2+ concentration ([Ca2+]i) triggers the expression of proto-oncogenes, which in turn direct the characteristic increase in protein synthesis. New results from perfused ferret hearts are presented demonstrating that [Ca2+]i increases as a direct consequence of an elevation in perfusion pressure. It therefore seems plausible that [Ca2+]i constitutes the crucial link between the initial stimulus for hypertensive hypertrophy (elevated perfusion pressure) and the secondary alterations in gene expression. Nevertheless, further investigation will be required to establish whether changes in [Ca2+]i are necessary or sufficient to stimulate myocardial cell growth.