PDE3 cyclic nucleotide phosphodiesterases are important in cyclic AMP (cAMP) and possibly cyclic GMP-mediated signalling in cardiac and vascular smooth muscle myocytes. Drugs that inhibit these enzymes have inotropic and vasodilatory actions that have proven useful in the short-term treatment of contractile failure and pulmonary hypertension in dilated cardiomyopathy (both ischaemic and idiopathic). With long-term usage, however, these drugs appear to increase mortality in treated patients through an as yet undetermined mechanism that is in some way attributable to an increase in intracellular cAMP content in cardiac myocytes. Several recent clinical trials have raised the possibility that these drugs may be used to advantage in dilated cardiomyopathy when they are administered in combination with beta-adrenoceptor antagonists, which act to lower intracellular cAMP content. In this review, the relevant basic and clinical data are examined and the possible justification for the combination of two therapies with seemingly opposite effects on intracellular cAMP content is considered.