Stress cardiomyopathy, also referred to as Takotsubo cardiomyopathy, is an increasingly recognized clinical syndrome characterized by acute reversible apical ventricular dysfunction. We hypothesize that stress cardiomyopathy is a form of myocardial stunning, but with different cellular mechanisms to those seen during transient episodes of ischemia secondary to coronary stenoses. In this syndrome, we believe that high levels of circulating epinephrine trigger a switch in intracellular signal trafficking in ventricular cardiomyocytes, from G(s) protein to G(i) protein signaling via the beta(2)-adrenoceptor. Although this switch to beta(2)-adrenoceptor-G(i) protein signaling protects against the proapoptotic effects of intense activation of beta(1)-adrenoceptors, it is also negatively inotropic. This effect is greatest at the apical myocardium, in which the beta-adrenoceptor density is greatest. Our hypothesis has implications for the use of drugs or devices in the treatment of patients with stress cardiomyopathy.