High altitude is a fascinating model of hypoxia effects on the human body but is also an extreme environment which directly influences millions of people who either travel to high altitude locations or live there permanently. A significant progress was 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 were published. In particular, more is known about the changes occurring in systemic blood pressure 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 blood pressure control and its changes at high altitude, mainly during the acute exposure. The evidence on blood pressure changes at rest and during exercise is discussed, as well as the underlying mechanisms and possible clinical implications.