Hot flashes are a common and disturbing adverse effect of hormonal therapy for cancer. Their pathophysiology is poorly understood. At present, the leading mechanistic hypothesis rests on the assumption that abrupt hormone deprivation will result in loss of negative feedback over hypothalamic noradrenaline synthesis. In this article we critically review the different theories used to explain this phenomenon. A better understanding of the pathophysiology of hot flashes may facilitate the development of new therapeutic approaches.