Hypertension is the primary contributor to cardiovascular disease, and the leading single contributor to all-cause mortality and disability worldwide. Despite apparent involvement of the immune system in hypertension, no feasible immune-based strategy to control blood pressure and associated target organ inflammation has yet emerged. This is due to our fragmented understanding of how hypertension links to specific immune activation. We and others have demonstrated that the bioactive phospholipid sphingosine-1-phosphate (S1P) critically contributes to disease mechanisms relevant to hypertension, atherosclerosis, heart failure, and stroke. We linked increments in plasma S1P to increasing systolic blood pressure and confirmed in experimental models an essential contribution of the S1P signaling axis to disease initiation.