In mammals, a thermogenic mechanism exists that increases heat production and consumes energy. Recent work has shed light on the cellular and physiological mechanisms that control this thermogenic circuit. Thermogenically active adipocytes, namely brown and closely related beige adipocytes, differentiate from progenitor cells that commit to the thermogenic lineage but can arise from different cellular origins. Thermogenic differentiation shares some features with general adipogenesis, highlighting the critical role that common transcription factors may play in progenitors with divergent fates. However, thermogenic differentiation is also discrete from the common adipogenic program and, excitingly, cells with distinct origins possess thermogenic competency that allows them to differentiate into thermogenically active mature adipocytes. An understanding of this thermogenic differentiation program and the factors that can activate it has led to the development of assays that are able to measure thermogenic activity both indirectly and directly. By combining these assays with appropriate cell models, novel therapeutic approaches to combat obesity and its related metabolic disorders by enhancing the thermogenic circuit can be developed.