6 young men had venous blood drawn during 4 experiments. The concentration of VIP in plasma increased markedly (from 1.8 (0--4.5) to 22.3 (7.8--43.8) pmol.1(-1), mean and range) during 3 h of mild bicycle exercise but not at all during an equivalent period of rest or during short term submaximal and maximal exercise. During 59 h of fasting, VIP increased from 3.6 (0.6--6.6) to 10.2 (6.6--13.8) pmol.1(-1) (p less than 0.05). The concentration of glucose in plasma decreased significantly during the prolonged exercise as well as during fasting. The known metabolic actions of VIP and the demonstrated increases in its plasma concentration during negative energy balance indicate that VIP is "a polypeptide of substrate need".