The lysophospholipid sphingosine 1-phosphate (S1P) is a pleiotropic signaling lipid present constitutively in plasma, and secreted locally at elevated concentrations at sites of inflammation. S1P maintains essential variable homeostatic functions in addition to inducing pathophysiology through the activation of five specific high-affinity G-protein-coupled receptors. Therefore, S1P can function as an extracellular rheostat regulating tonic and acutely evoked functions. Although S1P receptors can regulate lymphoid development and lymphocyte trafficking, and different opinions exist on the roles of receptor agonism and functional antagonism in regulating lymphocyte recirculation, this personal perspective highlights the pivotal control points regulated by constitutive and induced S1P receptor tone at vascular endothelial and lymphatic endothelial barriers, through which S1P agonism impacts on both innate and adaptive immunity. We also emphasize how specific, proof-of-concept chemical tools complement genetic approaches by enabling reversible perturbation of the S1P–S1P₁ receptor axis and, thus, clarifying in vivo mechanisms in the absence of developmental compensations.