Millions of patients worldwide are admitted for acute heart failure (AHF) each year and physicians caring for these patients are confronted with the short-term challenges of reducing symptoms while preventing end organ dysfunction without causing additional harm, and the intermediate-term challenges of improving clinical outcomes such as hospital readmission and survival. There are limited data demonstrating the efficacy of any currently available therapies for AHF to meet these goals. After diuretics, vasodilators are the most common intravenous therapy for AHF, but neither nitrates, nitroprusside, nor nesiritide have robust evidence supporting their ability to provide meaningful effects on clinical outcomes, except perhaps early symptom improvement. Recently, a number of novel agents with vasodilating properties have been developed for the treatment of AHF. These agents include serelaxin, natriuretic peptides (ularitide, cenderitide), β-arrestin-biased angiotensin II type 1 receptor ligands (TRV120027), nitroxyl donors (CXL-1020, CXL-1427), soluble guanylate cyclase modulators (cinaciguat, vericiguat), short-acting calcium channel blockers (clevidipine), and potassium channel activators (nicorandil). These development programmes range from the stage of early dose-finding studies (e.g. TRV120027, CXL-1427) to large, multicentre mortality trials (e.g. serelaxin, ularitide). There is an urgent need for agents with vasodilating properties that will improve both in-hospital and post-discharge clinical outcomes, and these novel approaches may provide opportunities to address this need.