We know a great deal about the receptors and signaling pathways in cardiomyocytes that contribute to hypertrophic growth. Although drugs that target them have proven effective in substantially reducing left ventricular hypertrophy and associated mortality, cardiovascular disease remains the leading cause of death in the West. Another approach may rest with exploiting naturally occurring regulators of maladaptive cardiac hypertrophy that have been identified in the past few years. These endogenous negative regulators can be grouped, for the most part, into those constitutively active but whose activity is decreased by hypertrophic stimulation, and those with little or no baseline activity that are activated by hypertrophic stimulation. Spanning both groups are 4 systems that converge on cyclic guanosine 3′, 5′-monophosphate (cGMP) generation, namely natriuretic peptides (ANP and BNP), kinins, nitric oxide (NO), and the angiotensin II type 2 receptor (AT₂). Although holding promise as a means for restricting hypertrophy, each of these signaling molecules has certain limitations that need to be overcome. What follows is an overview of research over the past 2 years, much of it published in Hypertension, which has dealt with the antihypertrophic action of this particular group of endogenous signaling molecules. Understanding the function and regulation of the antihypertrophic NO–cGMP system offers the promise of novel therapeutic strategies for treating cardiac hypertrophy and heart failure.