Excessive levels of catecholamines have long been known to be cardiotoxic, but less well known are their toxic effects on skeletal muscle. By using an antimyosin monoclonal antibody and quantitative methods to measure the extent of myocyte necrosis, and by employing modulators of adrenoceptors (ARs), including clenbuterol, bupranolol, propranolol, bisoprolol, atenolol, ICI-118551, phenoxybenzamine, prazosin, and yohimbine, the involvement of ARs in isoproterenol-induced myotoxicity was characterized. In the myocardium, the toxic effects were predominantly mediated via the β 1-ARs. In the soleus muscle, it was almost solely via the β 2-ARs. Myotoxicity was also observed in the myocardium when challenged with the β 2-AR agonist clenbuterol. This was found to be mediated via sympathetic presynaptic β 2-ARs, leading to enhanced release of norepinephrine. This effect was abolished by prior treatment with reserpine. The skeletal muscle was found to be more sensitive to the myotoxic effects than cardiac muscle at lower doses of β-AR agonists. These experiments introduce a new way of assaying β-AR antagonists by classifying them according to their ability to prevent catecholamine-induced myotoxicity. Further research along these lines may deepen understanding of which β-blockers work best in heart failure therapy.