Body temperature regulation involves a homeostatic balance between heat production and dissipation. Sympathetic agents such as 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) can disrupt this balance and as a result produce an often life-threatening hyperthermia. The hyperthermia induced by MDMA appears to result from the activation of the sympathetic nervous system (SNS) and the hypothalamic-pituitary-thyroid/adrenal axis. Norepinephrine release mediated by MDMA creates a double-edged sword of heat generation through activation of uncoupling protein (UCP3) along with alpha1- and beta3-adrenoreceptors and loss of heat dissipation through SNS-mediated vasoconstriction. This review examines cellular mechanisms involved in MDMA-induced thermogenesis from UCP activation to vasoconstriction and how these mechanisms are related to other thermogenic conditions and potential treatment modalities.