Every year millions of people fly to high-altitude destinations. They thereby expose themselves to specific high-altitude conditions. The hypoxic environment (low ambient oxygen availability) constitutes a major factor affecting health and well-being at high altitude. While the oxygen availability is already moderately reduced inside the aircraft cabin, this reduction becomes aggravated when leaving the plane at high-altitude destinations. Especially if not pre-acclimatized, the risk of suffering from high-altitude illnesses, e.g., acute mountain sickness, high-altitude cerebral or pulmonary edema, increases with the level of altitude. In addition, diminished oxygen availability impairs exercise tolerance, which not only limits physical activity at high altitude but may also provoke symptomatic exacerbation of pre-existing diseases. Moreover, the cold and dry ambient air and increased levels of solar radiation may contribute to adverse health effects at higher altitude. Thus, medical pre-examination and pre-flight advice, and proper preparation (pre-acclimatization, exercise training, and potentially adaptation of pharmacological regimes) are of utmost importance to reduce negative health impacts and frustrating travel experiences.