The heart is remarkably plastic, chang-ing its size, shape, and function in response to a wide variety of stimuli. Beyond birth, by far the greatest cardiac growth occurs by cellular hypertrophy, rather than hyperplasia. When normal cardiac size has been reached, additional changes in size can occur in response to stimuli such as hypertension, defective genes, or exercise, to name a few. Although some of this hypertrophy is adaptive, some of it is maladaptive and can ultimately result in cardiac failure, the largest health care burden in the United States. A great deal of attention has been paid to the molecular pathways of hypertrophy, and it is clear that they are complex, having many intersections. A series of observations has pointed toward calcineurin as a key mediator of cardiac hypertrophy, and two articles in this issue of PNAS have further underscored this assertion (1, 2). Calcineurin is a serine–threonine phosphatase that is activated by Ca 2-calmodulin. Calcineurin dephosphorylates nuclear factor of activated T cells (NFAT), which then translocates to the nucleus where it acts combinatorially with other transcription factors to activate downstream targets. A report by Molkentin et al. in 1998 demonstrated that an activated calcineurin could provoke massive cardiac hypertrophy and that the immunosuppressive agents, cyclosporin A (CsA) and FK506, could block this process (3). Further, expression of a downstream target of calcineurin, activated NFAT3, had the same effect and could be prevented by CsA and FK506 (3). These observations provoked heated arguments about the appropriateness of both calcineurin as a therapeutic target and immunosuppressants as drugs to prevent treat cardiac hypertrophy.