Abstract Rational use of phosphodiesterase inhibitors represents an ongoing controversy in contemporary pharmacotherapy for heart failure. In randomized clinical trials, phosphodiesterase inhibitors increased cardiac output at the expense of worsening the rates of sudden cardiac death and cardiovascular mortality. Preliminary findings from ongoing clinical and preclinical investigations of phosphodiesterase activity suggest that combined use of phosphodiesterase inhibitors with beta-adrenergic antagonists may prevent these adverse outcomes. Compartmentation of cyclic adenosine 3',5'-monophosphate signaling may prove critical in determining myocardial response to combination therapy.