Systemic hypoxia is associated with conditions like anemia, lung diseases, sleep disorders, breathing, and exposure to high altitude. The physiological responses including blood pressure regulation to acute, chronic, intermittent normobaric, and hypobaric hypoxia have been under intense investigation for the past many years; however, the regulatory mechanisms are incompletely understood. The available literature indicates a differential response to hypoxia in pulmonary versus systemic circulation. Multiple physiological and metabolic changes contribute towards high-altitude acclimatization; yet, in some individuals, exposure to high altitude could be life threatening due to maladaptation. There are a few studies on the prevalence of hypertension in high-altitude natives and sea-level dwellers exposed to high altitude (acute and chronic). Elevated blood pressure is an established risk factor for different cardiovascular disease and the evidence suggests that the blood pressure rises to a modest extent in patients with mild to moderate hypertension upon acute ascent to high altitude (Luks et al., Congenit Heart Dis 5:220-232, 2010), but there is no clear evidence on increased risk of complications due to increased systemic blood pressures. This book chapter reviews available literature on systemic blood pressure responses to high altitude. A. Sarybaev (*)