Traditionally, scientists and clinicians have explored peripheral physiological responses to acute hypoxia to explain the pathophysiological processes that lead to acute mountain sickness (AMS) and high-altitude cerebral edema (HACE). After more than 100 years of investigation, little is yet known about the fundamental causes of the headache and nausea that are the main symptoms of AMS. Thus, we review the evidence supporting a change in focus to the role of the central nervous system in AMS. Our justification is (i) that the symptoms of AMS and HACE are largely neurological, (ii) that HACE is considered to be the end-stage of severe AMS and was recently identified as a vasogenic edema, opening the door for a role for blood-brain barrier permeability in AMS, (iii) that new, non-invasive techniques make measurement of brain water levels and cerebral blood volume possible and (iv) that the available experimental evidence and theoretical arguments support a significant role for brain swelling in the pathophysiology of AMS. We believe that an examination of the responses of the central nervous system to acute hypoxia will reveal important new pathophysiological processes that may help explain AMS and HACE.