Cardiac hypertrophy results from increased mechanical load on the heart and through the action of neurohumoral mediators. ERK1/2 are known to be activated in response to almost every stress- and agonist-induced hypertrophic stimulus examined to date, suggesting the straightforward hypothesis that these kinases are required for promoting the cardiac growth response. However, recent data from genetically modified mouse models suggest a more complicated picture. For example, inducible expression of dual-specificity phosphatase 6, an ERK1/2-inactivating phosphatase, eliminated ERK1/2 phosphorylation in transgenic mice, but it did not diminish the hypertrophic response to pressure overload. Similarly, Erk1-/- and Erk2+/- mice showed no reduction in stimulus-induced cardiac growth in vivo. However, blockade or deletion of cardiac ERK1/2 did predispose the heart to decompensation and failure after long-term pressure overload. Thus, ERK1/2 signaling is not to be absolutely necessary for mediating cardiac hypertrophy, although it does appear to provide critical protective effects/signals during stress-stimulation.