The low pressure at high altitudes (above 2500 m) causes hypoxia (decreased oxygen) that affects people’s physiological and psychological characteristics. Specifically, hypoxia may affect the neural function of the brain, leading to severe cognitive deficits and a significant decline in memory function and attention. This article addresses the effect of human factors on transportation design and operation at high altitudes (HA), with some details on the Tibet-China region. Specifically, the paper first reviews the basic transportation-related concepts for high altitude, including oxygen and temperature levels, driver perception-reaction time, hazard perception, vehicle speed, and walking speed. Then, the transportation users affected by high altitudes are discussed, including drivers, pedestrians, cyclists, passengers, and others. Next, the impacts of human factors on highway design and operation for HA regions are discussed along with the research needs. Finally, recent innovations to address the challenges of HA transportation are presented, along with case studies comparing some human factors of the plateau and plain areas. This article represents a valuable reference for future research in HA regions to improve transportation design and safety