Although the upright position seems natural for humans, it is unique in the animal kingdom. For animals the heart is positioned at the level of the main part of the circulation, while for upright humans about 80% of the blood volume is positioned below the level of the heart. Accordingly, cardiac output is reduced in upright humans and the heart is operating at the ascending part of the Starling curve. A reduced cardiac output is of consequence for regional flow and may be surprisingly also for cerebral blood flow (CBF). That is the case although blood pressure at the level of the brain is virtually similar to the value in the supine position since blood pressure at the level of the heart increases when upright. It has been considered whether a reduction in the arterial carbon dioxide tension can explain the reduction in cerebral perfusion when upright. The end-tidal carbon dioxide tension is reduced markedly when humans are upright since the matsh been pulmonary perfusion and ventilation is enhanced. On the other hand, the reduction in the arterial carbon dioxide tension is comparatively modest and, at the most, has only a transient influence on CBF in upright humans. Thus, as demonstrated during physical exercise, both experimentally and in different patient populations, CBF is influenced not only by cerebral autoregulation and the arterial carbon dioxide tension but also by the ability to increase cardiac output. When upright, cerebral perfusion is affected by the reduction in cardiac output and only if the muscle pump provides sufficient venous return to the heart can cerebral perfusion and oxygenation be maintained.