Phosphodiesterases (PDEs) comprise a superfamily with 11 subfamilies. Within these families, more than 40 isoforms are expressed. Phosphodiesterase-3 inhibitors (PDE3i) are used as inotrope/vasodilators for acute heart failure (HF), and PDE5i for pulmonary hypertension and erectile dysfunction. Despite being studied for chronic HF, none of the PDEis have been presently approved for such an indication itself. The PDE3is milrinone (the PROMISE trial and OPTIME-CHF), raised safety concerns. Although low-dose intravenous milrinone with a beta-blocker is till proposed by some. Enoximone failed to show significant benefits in patients with severe chronic HF in a series of phase 3 clinical trials (ESSENTIAL 1, ESSENTIAL II, EMOTE, EMPOWER). Of the PDE5is, Sildenafil is the most extensively investigated, with proven efficacy in treating erectile dysfunction and pulmonary arterial hypertension, but it has only been tested in relatively small trials in the field of HFrEF, but shows some promise in HFpEF and in pulmonary hypertension complicating HF. Elucidation of the potential clinical role of PDEis on across the spectrum of HF phenotypes will require more definitive evidence from large-scale clinical trials.