Myocardial hypertrophy is an adaptational response of the heart to increased work load, but it is also associated with a high risk of cardiac mortality^,, due to its established role in the development of cardiac failure, one of the leading causes of death in developed countries. Multiple growth factors^, and various downstream signaling pathways involving, for example, ras, gp-130 (ref. ), JNK/p38 (refs. ,) and calcineurin/NFAT/CaM-kinase have been implicated in the hypertrophic response. However, there is evidence that the initial phase in the development of myocardial hypertrophy involves the formation of cardiac para- and/or autocrine factors like endothelin-1, norepinephrine or angiotensin II (refs. ,), the receptors of which are coupled to G-proteins of the G_q/11-, G_12/13- and G_i/o-families^,,. Cardiomyocyte-specific transgenic overexpression of α₁-adrenergic or angiotensin (AT₁)-receptors as well as of the G_q α-subunit, Gα_q, results in myocardial hypertrophy^,,,. These data demonstrate that chronic activation of the G_q/G₁₁-family is sufficient to induce myocardial hypertrophy. In order to test whether G_q/G₁₁ mediate the physiological hypertrophy response to pressure overload, we generated a mouse line lacking both Gα_q and Gα₁₁ in cardiomyocytes. These mice showed no detectable ventricular hypertrophy in response to pressure-overload induced by aortic constriction. The complete lack of a hypertrophic response proves that the G_q/G₁₁-mediated pathway is essential for cardiac hypertrophy induced by pressure overload and makes this signaling process an interesting target for interventions to prevent myocardial hypertrophy.