First described in 1926 as a hormone of pregnancy secreted from the corpus luteum to soften the cervix and relax the pelvic ligaments at term it is only recently that the chemistry, physiology and molecular biology of the hormone has been elucidated.  Immunoassay established that the levels of relaxin in the blood rose dramatically just prior to parturition in most mammalian species --- except the human where the levels peaked in the first trimester and thereafter declined.  Not surprisingly, clinical trials of relaxin in the human failed to show efficacy as a cervical softening agent.  Although a fascinating hormone to study in that everything about it is surprising and unexpected a series of failed clinical trials in the human for various indications has led many investigators to the view that the peptide has little clinical relevance in the human.  However, based on early observations of potent vasoactive actions of relaxin and the presence of specific receptors in the heart, a recent trial by Novartis of relaxin for the treatment of acute heart failure reached significance in Phase 3 trials with positive clinical outcomes. We now know that there are 7 distinct relaxin-like peptides that are structurally related to insulin. Each of the peptides have different physiological roles with actions in male and female reproduction, in the brain as a neuromodulator and as a cardiac stimulant and antifibrotic agent. The availability of synthetic analogues of the relaxin peptides with specific agonist and antagonist activities has been particularly useful in establishing the location and possible role of a member of the relaxin family know as RLX-3 in the central nervous system. Recent studies from the Florey Institute and our collaborators have characterized 4 distinct G protein-coupled receptors for the relaxin peptides and their signal transduction pathways which provide a clearer picture of the mode of action of the hormone and suggest possible new therapeutic opportunities.