There is considerable experimental evidence that high-density lipoprotein (HDL) cholesterol and the principal high-affinity HDL receptor scavenger receptor B type I (SR-BI) afford cardiovascular protection. However, the fundamental mechanisms underlying the protection remain complex and not well understood. Recent work in cell culture indicates that the HDL-SR-BI tandem stimulates endothelial cell migration. Further studies have revealed that this entails Src-mediated, phosphatidylinositol 3-kinase-mediated, and mitogen-activated protein kinase-mediated signaling that leads to the activation of Rac guanosine triphosphate hydrolase and the resultant rearrangement of the actin cytoskeleton. Furthermore, assessment of reendothelialization after perivascular electric injury in mice indicates that HDL-SR-BI-mediated stimulation of endothelial migration is operative in vivo. Recent additional work in mice also indicates that HDL activates the recruitment of endothelial progenitor cells into the intimal layer in the setting of endothelial injury. As such, signaling initiated by HDL-SR-BI promotes endothelial repair, and this novel mechanism of action may be critically involved in the impact of the lipoprotein on vascular health and disease.