Skin blood flow and sweating are two key thermoregulatory responses that help regulate body temperature in heat-stressed human beings. Adjustments in skin blood flow and sweating in response to thermal stimuli are mediated by local and reflex neural mechanisms (Johnson et al. 2014). Local thermosensitive mechanisms are important, as the application of heating to a particular area of the skin results in a localized elevation of blood flow and sweating in the heated skin. However, the precise pathways underpinning heat loss responses to heat stress, particularly those involving ATP as a mediator signal, are not fully established or understood. Heat stress-induced hyperthermia is associated with increases in intravascular ATP and accompanied by vasodilatation of the human skin and deep limb tissue vasculatures (Pearson et al. 2011; Heinonen et al. 2011). This supports a mechanistic coupling between the rise in intravascular ATP and the concomitant increase in local perfusion (Kalsi & Gonzalez-Alonso, 2012). However, sympathetic cholinergic nerves, which are known to modulate heat loss responses, co-release ATP with acetylcholine. These sensory nerves are therefore potential sources of ATP in the dermal interstitium. This raises the possibility that ATP may act as a thermal mediator signal, involved in the regulation of vasomotor and sudomotor activity in conditions of hyperthermia. In support of this idea, intradermal administration of ATP has been shown to induce cutaneous vasodilatation in human beings in vivo (Wingo et al. 2010), but the downstream mediators and its effect on sweating have not been investigated. Mechanistically, ATP can bind to P2Y purinergic receptors located in the cutaneous vasculature, and the sweat gland, and trigger cutaneous vasodilatation and increase sweating via at least three pathways: (i) activation of nitric oxide synthase (NOS), (ii) activation of cyclooxygenase (COX) and/or (iii) via the action of the ATP degradation compound adenosine. In this issue of The Journal of Physiology, Fujii et al. (2015) report the findings from an outstanding series of integrative physiology studies in human beings. The authors systematically investigated the roles of NOS and COX in the cutaneous vascular and sweating responses to intradermal administration of ATP, as well as the contribution of adenosine to ATP-induced skin vasodilatation in vivo. A major finding was that intradermal ATP infusion at a rate of 120 and 1200 nmol min−1 causes significant cutaneous vasodilatation. Co-infusion of the NOS inhibitor Nω–nitro-l-arginine (l-NNA) blunted about one-fourth of the ATP-evoked vasodilator response, implicating NOS as a mediator. The study also excluded two other potential regulatory pathways; blockade of COX or adenosine with co-infusion of ketorolac or theophylline did not alter the vasodilator response to intradermal ATP infusion. Lastly, none of the study protocols increased sweating. These observations collectively advance the basic physiological understanding of the control of skin blood flow and sweating. By showing that part of the vasodilator response to intradermal ATP administration is mediated by NOS and by providing conclusive evidence that ATP does not directly increase sweating in vivo, these data suggest that skin blood flow and sweating are not regulated by the same thermal mediator signal. The physiological relevance of interstitial ATP on thermal hyperaemia was not addressed in the study of Fujii et al. (2015). ATP needs to accumulate in the dermal interstitium for this ubiquitous molecule to exert its cutaneous vasodilator effects directly by binding to interstitial purinergic receptors. However, recent evidence suggests that local heating does not result in an accumulation of ATP in the interstitial space of human skin, and thus such accumulation is not necessary for local thermal hyperaemia to occur (Gifford et al. 2012). This observation and the additional finding by Fujii and coworkers that the intradermal administration of ATP at low infusion rates (0.12–12 nmol min−1) does not increase skin blood flow indicate that under physiological conditions ATP-mediated cutaneous vasodilatation is more likely to occur via the activation of purinergic receptors residing in the vascular endothelium. Although further research is needed to establish the physiological relevance of intravascular versus interstitial ATP in thermoeffector activity, the timely investigation of Fujii et al. (2015) highlights the capacity of ATP to be the elusive thermal mediator igniting skin perfusion in heat-stressed human beings, but not the signal that increases sweating.