BRS3 (bombesin receptor subtype 3) is an orphan G-protein-coupled receptor that activates phosphatidylinositol-calcium second messenger systems 1. Primary functions include regulation of energy and glucose homeostasis, with BRS3 knockout mice developing obesity, hypertension, impaired glucose metabolism, and hyperphagia 1. The receptor is widely expressed in the central nervous system and peripheral tissues 2, including hypothalamic populations involved in homeostatic regulation 3. Mechanistically, BRS3 activation stimulates phospholipase C with phosphoinositide breakdown and calcium mobilization, and can activate ERK/MAPK signaling and EGFR transactivation in certain cell types 4. BRS3 shows distinct receptor-coupling relationships and species-dependent differences from peptide agonists 2. Diseased relevance is significant: BRS3 is frequently overexpressed in lung cancer cells (92% of tested lines) where it promotes cell growth 4, and overexpression occurs in other malignancies 5. BRS3 agonists demonstrate promise for treating obesity and diabetes 1, though cardiovascular side effects with centrally-acting agents require investigation 1. Selective BRS3 agonists represent novel therapeutic candidates for metabolic disorders and potential imaging/cytotoxic agents for cancer 14.