Blood lymphocyte numbers, which are maintained by recirculation through secondary lymphoid organs, are essential for the efficient development of immune responses. Recirculating populations of B and T lymphocytes are regulated by the sphingosine‐1‐phosphate (S1P) receptor‐dependent control of lymphocyte egress. T‐cell egress from thymus into blood, egress from lymph node and Peyer's patch into lymph, and B‐cell egress into lymph are rapidly and completely inhibited by agonism of S1P receptors. Mesenteric lymph nodes show log‐jamming of lymphocytes subjacent to sinus‐lining endothelium. Agonism of S1P receptors produces rapid peripheral blood lymphopenia, which is maintained in the presence of receptor agonist. Effector CD4⁺ and CD8⁺ T cells, produced by clonal expansion in draining lymph node in response to antigen, are sequestered in lymph node and fail to reach the peripheral blood. The S1P receptor system may represent an early physiological link between the non‐specific inflammatory response and the alteration of lymphocyte traffic through draining lymph nodes. Pharmacological subversion of the S1P receptor system, through systemic S1P agonist‐induced inhibition of lymphocyte egress, suppresses antigenic responses to peripheral, but not to systemically, delivered antigen. This inhibition induces significant immunosuppression in models of transplantation and autoimmune tissue damage that may prove to be of clinical benefit.