Sphingosine 1-phosphate (S1P), a product of sphingomyelin metabolism, is enriched in the circulatory system whereas it is estimated to be much lower in interstitial fluids of tissues. This concentration gradient, termed the vascular S1P gradient appears to form as a result of substrate availability and the action of metabolic enzymes. S1P levels in blood and lymph are estimated to be in the μM range. In the immune system, the S1P gradient is needed as a spatial cue for lymphocyte and hematopoietic cell trafficking. During inflammatory reactions in which enhanced vascular permeability occurs, a burst of S1P becomes available to its receptors in the extravascular compartment, which likely contributes to the tissue reactions. Thus, the presence of the vascular S1P gradient is thought to contribute to physiological and pathological conditions. From an evolutionary perspective, S1P receptors may have co-evolved with the advent of a closed vascular system and the trafficking paradigms for hematopoietic cells to navigate in and out of the vascular system.