The presence of differences in physiological response to a lowered inspired Po2 mediated by hypobaric hypoxia (HH) or normobaric hypoxia (NH) is controversial. This review examines the brief, acute, and subacute respiratory, cardiovascular, and subjective symptom response to intermediate and severe hypoxic exposure in NH and HH. Brief exposures lead to similar physiological responses; this is not the case in acute/subacute exposures. Extrapolating data from NH studies to HH in longer exposures is inappropriate as physiological responses to hypoxia seem to be influenced by the prevailing ambient pressure, especially in chronic exposures where acute mountain sickness severity is greater in HH than NH. Explanations for the discrepancy between the two modalities include differences in ventilatory patterns, alveolar gas disequilibrium, and dissimilar acute hypoxic ventilatory responses. Awareness and consideration of these key differences between NH and HH is essential to their proper application to kinesiology, altitude, and aviation medicine.