Sphingolipids, in particular sphingosine kinase (SphK) and its product sphingosine-1-phosphate (S1P), are now recognized to play an important role in regulating many critical processes in endothelial cells. Activation of SphK1 is essential in mediating the endothelial proinflammatory effects of inflammatory cytokines such as tumor necrosis factor (TNF). In addition, S1P regulates the survival and proliferation of endothelial cells, as well as their ability to undergo cell migration, all essential components of angiogenesis. Thus the inflammatory and angiogenic potential of the endothelium is in part regulated by intracellular components including the activity of SphK1 and levels of S1P. Herein a review of the sphingomyelin pathway with a particular focus on its relevance to endothelial cell biology is presented.