The temporal link between cardiac hypertrophy and progressive myocardial failure has been recognized for some time, although mechanistic connections have been elusive. More than 100 years ago, Sir William Osler described three classic stages of cardiac hypertrophy, which culminate in “broken compensation.” 1 Much research in recent years has focused on identifying specific hypertrophic stimuli and dissecting the corresponding signaling pathways to elucidate the events responsible for this maladaptive transition. The development and widespread adoption of molecular techniques to modify the genome, chiefly in small mammals, have fueled this search and have provided investigators a means to test the physiological consequences of single gene defects, engineered in vivo. Toward this end, both gain-and loss-of-function mutations have been used in efforts to understand the biochemical pathways and molecular mechanisms underlying the transition from cardiac hypertrophy to failure, at least in mice, culminating in a robust and stillgrowing array of transgenic models with a cardiomyopathic phenotype similar in many respects to the human disease state.