High altitude is a fascinating model of hypoxia effects on the human body, but it is also an extreme environment that directly influences millions of people who either travel to high altitude locations or live there permanently. A significant progress has been made over the past decades in the understanding of physiological background of responses to altitude, and recently, a number of studies regarding clinical aspects of high-altitude exposure have been published. In particular, more is known about the changes in systemic blood pressure (BP) in individuals exposed to high altitude as well as on the effects of antihypertensive drugs in this setting. The present article provides an overview of principal physiological and clinical aspects related to systemic BP control and its changes at high altitude, mainly during the acute exposure. The evidence on BP changes at rest and during exercise is discussed, as well as the underlying mechanisms and possible clinical implications.