Purpose of review Atherosclerotic cardiovascular diseases continue to be a significant global cause of death. Despite the availability of efficient treatments, there is an ongoing need for innovative strategies to lower lipid levels, especially for individuals experiencing refractory dyslipidemias or intolerable adverse effects. Based on human genetic findings and on mouse studies, the G protein-coupled receptor 146 (GPR146) emerges as a promising target against hypercholesterolemia and atherosclerosis. The present review aims at providing a thorough summary of the latest information acquired regarding GPR146, encompassing genetic evidence, functional insights, and its broader implications for cardiometabolic health. Recent findings Human genetic studies uncovered associations between GPR146 variants, plasma lipid levels and metabolic parameters. Additionally, GPR146's influence extends beyond lipid regulation, impacting adipocyte differentiation, lipolysis, and inflammation pathways. Despite GPR146's orphan status, ongoing efforts to deorphanize it, suggest a potential ligand with downstream effects involving Gαi coupling. Summary Here, we outline and deliberate on recent progress focused on: enhancing comprehension of the effects of inhibiting GPR146 in humans through genetic instruments, evaluating the extra-hepatic functions of GPR146, and discovering its natural ligand(s). Grasping these biological parameters and mechanisms is crucial in the exploration of GPR146 as a prospective therapeutic target.