Background: Thermogenic brown and beige adipocytes are recognized for their unique capacity to consume extraordinary levels of metabolites and lipids from the blood to fuel heat-producing catabolic processes [1–7]. In humans, the functions of thermogenic adipocytes are associated with cardiometabolic protection and improved glycemic control [8–13]. Consequently, engaging these macronutrient-consuming and energy-dissipating activities has gained attention as a promising therapeutic strategy for counteracting metabolic diseases, such as obesity and diabetes. Scope of review: In this review, we highlight new advances in our understanding of the physiological role of G protein-coupled receptors (GPCRs) in controlling thermogenic adipocyte biology. We further extend our discussion to the opportunities and challenges posed by pharmacologically targeting different elements of GPCR signaling in these highly specialized fat cells. Major conclusions: GPCRs represent appealing candidates through which to harness adipose thermogenesis. Yet safely and effectively targeting these druggable receptors on brown and beige adipocytes has thus far proven challenging. Therefore, continued interrogation across the GPCR landscape is necessary for future leaps within the field of thermogenic fat biology to unlock the therapeutic potential of adipocyte catabolism.