Adipose thermogenesis is the energy lost as heat through metabolism of macronutrients in specialized fat cells, or adipocytes (1). This program is activated by neuronal, hormonal, and metabolic cues in response to cold temperature, dietary excess, and time of day. The capacity of thermogenic adipocytes to dissipate macronutrient calories as heat is vital to body temperature defense in rodents and, likely, human infants. In adult humans, this tissue serves as a catabolic "sink" to burn off excess blood macronutrients, and its activity is linked to improved body weight regulation, glucose and lipid control, and cardiometabolic health (2). Stimulating adipose thermogenesis is an appealing strategy to counteract metabolic disruptions, such as obesity and type 2 diabetes, but has yet to yield a pharmacotherapy that is both safe and efficacious. However, deeper interrogation of heat-producing macronutrient pathways and the emerging roles of macronutrients in shaping thermogenic capacity offer the possibility of finally unlocking this distinct biology.