Water drinking elicits profound pressor responses in patients with impaired baroreflex function and in sinoaortic-denervated mice. Healthy subjects show more subtle changes in heart rate and blood pressure with water drinking. The water-induced pressor response appears to be mediated through sympathetic nervous system activation at the spinal level. Indeed, water drinking raises resting energy expenditure in normal weight and obese subjects. The stimulus setting off the response is hypoosmolarity rather than water temperature or gastrointestinal stretch. Studies in mice suggest that this osmopressor response may involve transient receptor potential vanniloid 4 (Trpv4) receptors. However, the (nerve) cell population serving as peripheral osmosensors and the exact transduction mechanisms are still unknown. The osmopressor response can be exploited in the treatment of orthostatic and postprandial hypotension in patients with severe autonomic failure. Furthermore, the osmopressor response acutely improves orthostatic tolerance in healthy subjects and in patients with neurally mediated syncope. The phenomenon should be recognized as an important confounder in cardiovascular and metabolic studies.