Plasma high-density lipoprotein (HDL) is a potent anti-atherogenic factor, a critical role of which is thought to be reverse cholesterol transport through the lipoprotein-associated apolipoprotein A-I (apoA-I). HDL also carries a potent bioactive lipid mediator, sphingosine 1-phophate (S1P), which exerts diverse physiological and pathophysiological actions in a variety of biological systems, including the cardiovascular system. In addition, HDL-associated apoA-I is known to stimulate intracellular signaling pathways unrelated to transporter activity. Mounting evidence indicates that multiple antiatherogenic or anti-inflammatory actions of HDL independent of cholesterol metabolism are mediated by the lipoprotein-associated S1P through S1P receptors and by apoA-I through scavenger receptor class B type I.