In 1890, Koch defined postulates which formed the intellectual cornerstone for the next century of advances in microbiology and ultimately led to the discovery of the infectious basis for anthrax, cholera, and tuberculosis. ly, two independent studies have shown that increasing the peak intracellular calcium transient can inhibit progression of heart failure in both genetic and acquired forms of cardiomyopathy (14, 17). In fact, ablating the endogenous brake on calcium cycling, phospholamban, can completely prevent the onset of cardiac hypertrophy and block the induction of atrial natriuretic factor in a mouse model of dilated cardiomyopathy (14). Because the decreased contractile function seen in the CaM kinase transgenic lines most likely reflects a decrease in the calcium transient, it will be important to characterize the compartmentalization of the calcium signal in the hypertrophied and failing heart. Doubly transgenic animals have proved difficult to generate from crosses between the CaM kinase and calcineurin mouse lines, most likely because the α-myosin heavy chain promoter drives expression of both gene products at high levels in the fetal and the adult heart (18), leading to early lethality. For this reason, it will be critical to determine which aspects of the observed phenotypes in the CaM kinase transgenic line represent developmental effect on myocyte survival or morphogenesis and which derive from postnatal effects of the exogenous kinase. Finally, and perhaps most importantly, it will ultimately become necessary to determine whether the observed phenotypes reflect a role of the endogenous CaM kinase genes in the activation of biomechanical stress–induced hypertrophy, or if they arise in part from nonspecific effects of the 50-to 100-fold overexpression of a constitutively active protein. With regard to this last point, there is a diverse and rapidly growing list of genes that can trigger features of hypertrophy and associated cardiomyopathy after their cardiac-specific expression (19–49)(Table 1), suggesting that multiple pathways can activate this complex adaptive response. As in the present study, in most of these cases, there are additional in vitro and in vivo data that support their role in the pathogenesis of hypertrophy. Accordingly, it is highly likely that these effects reflect a direct or indirect role for many of these genes in the hypertrophic response, a view that is supported by the fact that each of the cardiac phenotypes has distinct characteristics at the molecular, morphological, and physiological levels. However, discriminating between end points that arise strictly as a result of a signaling event from those that reflect nonspecific cardiac injury, presumably due to the disruption of the signaling stoichiometry in multiple pathways, could be a vexing problem. Death of cardiac myocytes may trigger not only postischemic heart failure, but also a transition between compensatory hypertrophy and dilated cardiomyopathy (50). As Izumo et al.(51) have shown, even the overexpression of the reporter gene GFP causes cardiotoxicity and cardiomyopathy when placed under the control of the αmyosin heavy chain promoter. For this reason, the precise role of many of these putative hypertrophy genes may have been obscured by extraordinarily high levels of transgene expression. A case in point is the large body of work, which has focused on the role of the calcineurin-NFAT pathway in cardiac hypertrophy (12, 13, 33, 52–54). Compelling data in transgenic mice (12), coupled with inhibition of the in vivo pressure overload response by cyclosporin, formed a cornerstone in support of a primary role for calcineurin as part of a final common pathway in hypertrophy …