Brain blood flow (BBF) is critical for maintaining oxygen and substrate supply to the brain and is secured by several mechanisms, of which the partial pressure of arterial carbon dioxide, mean arterial pressure, and cerebral metabolism are the most important. The historical controversy about whether BBF is altered during exercise relates to the methodology used to quantify BBF. The present understanding is that when the brain is activated, as during exercise, an increment in BBF enhances cerebral oxygenation. An increase in near-infrared spectroscopy determined oxygenated hemoglobin (Hb) and a reduction in deoxygenated Hb in response to a motor task support that cerebral oxygenation exceeds the increase in O2 demand. During exercise, the arterial O2 content may increase and, together with increased BBF in response to cerebral activation, enhance brain oxygen delivery. The cerebral hyperperfusion in the early phase of exercise may be an important precaution because BBF declines in the later stages of exercise, mainly by the dominant negative effect of progressive hypocapnia on BBF. Brain function deteriorates when its oxygenation is reduced by more than 10% from the resting level. In contrast, skeletal muscles tolerate oxygen desaturation down to 10%. During exercise, reduced cerebral oxygenation precedes development of so-called central fatigue. Debate continues on whether the subsequent reduction in cerebral oxygenation in the later stages of exercise could play a role in the development of central fatigue with reduced motor drive to working muscles. Cardiac output may also influence BBF during exercise. Inability to increase cardiac output sufficiently during exercise may jeopardize cerebral perfusion and thereby the ability of the central nervous system to drive the motoneurons adequately. This is illustrated by the BBF response to exercise in subjects with type 2 diabetes which could contribute to their high perceived exertion.