ABSTRACT Since more than 40% of all clinically-available drugs target G-protein coupled receptors (GPCRs), there is great interest in learning more about this family of proteins in order to discover new therapeutic targets. When considering the different classes of proteins encoded by the human genome that are predicted to be pharmacologically-tractable, a remarkable one quarter represent GPCRs. And yet, of the ~345 non-odorant GPCRs a large proportion remain orphan—with no known ligand—or have uncharacterized physiological functions. Since we have a dearth of pharmacological targets for lymphatic vessels, it stands to reason that focused efforts to explore and characterize the lymphatic “GPCRome” is a worthwhile endeavor. We have identified 3 orphan GPCRs that are IDG-eligible target proteins in the Illuminating the Druggable Genome (IDG) Project. We propose to develop and use in vitro and animal-based systems to further characterize the expression and activation of these GPCRs in the lymphatic vasculature. Our results will further the overall goals of the IDG Consortium and reveal novel physiological pathways and potential therapeutic targets for the modulation of lymphatics, which remains an understudied research area with unmet clinical needs.