Over the past few decades, research on the peptide hormone, relaxin, has significantly improved our understanding of its biological actions under physiological and diseased conditions. This has facilitated the conducting of clinical trials to explore the use of serelaxin (human recombinant relaxin). Acute heart failure (AHF) is a very difficult to treat clinical entity, with limited success so far in developing new drugs to combat it. A recent phase-III RELAX-AHF trial using serelaxin therapy given during hospitalization revealed acute (ameliorated dyspnea) and chronic (improved 180-day survival) effects. Although these findings support a substantial improvement by serelaxin therapy over currently available therapies for AHF, they also raise key questions and stimulate new hypotheses. To facilitate the development of serelaxin as a new drug for heart disease, joint efforts of clinicians, research scientists and pharmacological industries are necessary to study these questions and hypotheses. In this review, after providing a brief summary of clinical findings and the pathophysiology of AHF, we present a working hypothesis of the mechanisms responsible for the observed efficacy of serelaxin in AHF patients. The existing clinical and preclinical data supporting our hypotheses are summarized and discussed. The development of serelaxin as a drug provides an excellent example of the bilateral nature of translational research.