Endothelial inflammation is an important risk factor in the initiation and development of vascular disease. Therefore, signaling cascades and patho-physiological outcomes of endothelial inflammation are important questions in vascular biology. Recent studies suggest that sphingosine-1-phosphate receptor subtype 2 (S1PR2) signaling in endothelial cells (ECs) play a critical role in endothelial inflammation. For example, ECs present in atherosclerotic plaques exhibit senescence phenotype. Levels of S1PR2 are markedly increased in cultured senescent ECs and in lesion regions of atherosclerotic endothelium. Also, inflammatory cytokines and mechanical flow stress profoundly increase S1PR2 levels in ECs. Inhibition of endothelial S1PR2 signaling diminishes endothelial senescence-associated functional impairments and atherogenic stimuli-induced endothelial activation. In contrast, activation of endothelial S1PR2 stimulates the production of pro-inflammatory chemokines/cytokines and lipid mediators in ECs. In this article, we will review signaling and functions of sphingosine-1-phosphate (S1P) receptors in endothelial biology, with particular focus on endothelial S1PR2 signaling-mediated endothelial inflammation.