The primary function of the cardiovascular system is to supply oxygen to tissues and organs in the body. When muscles contract the aerobic demands are quickly met by an increase in oxygen delivery both at the systemic and the regional levels. The match is very close, but it takes above 30 s for this elevation in oxygen delivery to occur. A multitude of factors behind this very early onset of exercise hyperaemia is discussed with mechanical factors presently being most in focus. This relates both to the pumping action of the contraction and to the direct activation at the vasculature level. To what extent locally produced substances also contribute to this early vasodilation is also a matter of controversy. In our recent experiments, using blockers of NOS (L-NMMA or L-NAME) and the enzymes producing EETs (Sulpaphenozole) or prostaglandins (indomethacin), the elevation in muscle blood flow is considerably slower and so is the oxygen uptake. This points at a role for "classical" vasodilation substances also at onset of exercise. Moreover, it appears that there is a link between the regulation of the oxygen uptake and the oxygen supply, also in this phase of the exercise. Furthermore, the red blood cells and a possible ATP release have been proposed as regulatory factors, but this has to be confirmed in further studies in humans where specific ATP receptor blockers can be used.