As obesity and obesity-associated diseases become more prevalent in western societies, new methods to promote weight-loss and protect patients from the dangerous consequences of excess adipose tissue are needed. While both researchers and clinicians previously turned to chemical uncouplers for many decades to create a negative energy balance and thus promote weight-loss, these compounds proved to be extremely dangerous treatment options, even when taken in mild dosages. Substances like 2-4 dinitrophenol (DNP), were able to significantly induce weight loss, however many life-threatening conditions such as fatal hyperthermia are commonly attributed to these uncoupling agents. Recently, with the discovery of natural brown/beige fat reservoirs in humans, many members of the medical community have become heavily invested in the targeting of more localized, less systemic uncoupling tissues. The action of UCP-1 in human thermogenic adipose introduces an opportunity to harness a natural, yet futile cycle, and hence boost a patient’s basal metabolism without ultimately compromising their long-term health. Many challenges remain before such a treatment is viable, including deciphering the biochemical pathways that induce brown fat thermogenesis. It appears that several uncoupling signals may govern the genetic programs that lead to this thermogenic activity, and the "browning" of white adipose stores in humans. Particularly in the last ten years, many studies have uncovered new components of the thermogenic program by ablating target genes in mice. While a direct pathway of thermogenic activation does exist when subjects are placed in a cold environment, a successful, high-adoption, anti-obesity treatment through a thermogenic regimen will likely involve a gene-therapy or protein-based biopharmaceutical intervention. It is conceivable that thermogenic manipulation could play a significant role in the battle against obesity and obesity-associated diseases, however a significant intellectual breakthrough in appetite suppression and/or appetite management (i.e. a successful intervention of the orexigenic and anorexigenic physiological pathways) could in theory supplant this approach.