Blood flow to skeletal muscle is regulated by a balance between, on one hand, sympathetic activity and locally formed vasoconstrictors and, on the other hand, locally formed vasodilators and sympatholytic compounds. During exercise, a number of vasodilators have been shown to contribute to the marked increase in blood flow to the active muscle and, importantly, interactions between these compounds appear to be essential for the precise regulation of blood flow. We and others have studied interactions between compounds including nitric oxide (NO), adenosine, ATP, prostacyclin and endothelial derived hyperpolarizing factor (EDHF). These studies have revealed that the potent vasodilating effects of both ATP and adenosine are mediated by NO and prostacyclin whereas the role for EDHF remains more obscure. It furthermore appears that prostacyclin can either promote or inhibit NO formation, depending on the conditions. Another observation of interest is that adenosine infused arterially also leads to an increased formation of NO and prostaglandins in the skeletal muscle interstitium, suggesting a bidirectional release of these vasodilators. Main questions that remain to be elucidated in this area are why so many different activators of NO synthesis are required and whether the different activators have separate roles depending on the actual physiological circumstances.