G protein-coupled receptors are central regulators in cardiovascular biology and are targeted by frontline therapies for cardiovascular disease including hypertension and heart failure, e.g. ß blockers and angiotensin receptor antagonists. Nevertheless, we only know the cardiovascular roles for a small fraction of the GPCR family, which suggests that there is tremendous scope for innovative research in this area. I have recently spearheaded a large multidisciplinary research effort to discover new peptide ligands that activate orphan receptors, for which the endogenous agonists and in most cases, biological function are unknown. Leveraging the wealth of bioinformatic data on human class A GPCRs, we identified common features for known peptide receptors that enabled prediction of peptide-binding orphan GPCRs. In parallel, we used statistical and machine learning analyses to identify putative peptide ligands. We then used a multifaceted experimental approach to capture orphan receptor responses, which were extensively validated using a range of cell signalling assays. In all, we tested our peptide library against 67 orphan GPCRs and 27 known peptide receptors. In addition to potential new ligands for nine known peptide GPCRs, we definitively paired five different orphan GPCRs with 17 peptides, and discovered potential new ligands for five further receptors. These discoveries have opened entirely new lines of enquiry on the biological functions of these receptors. In particular, two of these peptide and orphan GPCR pairings have compelling links to fibrosis and heart failure that mandate further investigation. My current research is building upon my orphan GPCR discoveries to elucidate their cardiovascular function, utilising a stem-cell derived human cardiac organoid platform pioneered in the Cardiac Bioengineering Group at QIMR Berghofer Medical Research Institute. These findings show that different peptides can drive changes in specific cardiac contraction parameters associated with cardiovascular disease.