Hormones and neurotransmitters may mediate common responses through receptors that couple to the same class of heterotrimeric guanine nucleotide–binding (G) protein. For example, several receptors that couple to G_q class proteins can induce cardiomyocyte hypertrophy. Class-specific inhibition of G_q-mediated signaling was produced in the hearts of transgenic mice by targeted expression of a carboxyl-terminal peptide of the α subunit Gα_q. When pressure overload was surgically induced, the transgenic mice developed significantly less ventricular hypertrophy than control animals. The data demonstrate the role of myocardial G_q in the initiation of myocardial hypertrophy and indicate a possible strategy for preventing pathophysiological signaling by simultaneously blocking multiple receptors coupled to G_q.