In heart failure, the sympathetic nervous system is activated. The increased release of norepinephrine from the heart and the elevated levels of circulating catecholamines produce a downregulation of myocardial beta 1-adrenoceptors. In ischemic cardiomyopathy and mitral valve disease, a downregulation of beta 2-adrenoceptors has been observed also. The beta-adrenoceptor downregulation closely correlates to the reduced positive inotropic effects of beta-adrenoceptor agonists. In addition, an increase of the inhibitory guanine-nucleotide binding protein (Gi alpha) has been observed, while the levels of the stimulatory guanine-nucleotide binding protein (Gs alpha), the activity of the catalyst and the anti-adrenergic effects of A1-adenosine receptor- or m-cholinoceptor stimulation remain unchanged in the failing human heart. The increase of Gi alpha correlated closely to the reduced positive inotropic responses to the cAMP-phosphodiesterase inhibitor milrinone. In the failing human heart, the beta-adrenoceptor downregulation and the increased expression of Gi alpha represent pathobiochemical alterations which are involved in the reduced effects of cAMP-dependent positive inotropic agents. The therapeutic reversal of these pathobiochemical alterations is a future promise in the treatment of heart failure.