Novel treatment of congestive heart failure (HF) involves utilizing unique pathways to improve upon contemporary therapies. Increasing the availability of cyclic guanosine monophosphate (cGMP) by inhibition of phosphodiesterase-5 (PDE5) is a relatively new, but promising therapeutic strategy. Preclinical studies suggest a favorable myocardial effect of PDE5 inhibitors by blocking adrenergic, hypertrophic and pro-apoptotic signaling, thereby supporting their use in HF. The clinical benefits of acute and chronic PDE5 inhibition on lung diffusion capacity, exercise performance and ejection fraction in humans are emerging and appear promising. Larger, controlled trials are now on-going to assess the safety, efficacy and tolerability of PDE5 inhibitors on morbidity and mortality in patients with both systolic and diastolic heart failure. If the results of these trials are positive, a new avenue for the treatment of HF will open, which will help curtail the societal effects of this costly and morbid disease.