The endoplasmic reticulum (ER) is the major organelle in cell for proper protein folding and trafficking to other organelles, lipid synthesis and calcium regulation. ER dysfunction is caused by various physical and biochemical insults such as excess nutrients, glucose deprivation, inflammatory status and perturbation of calcium homeostasis. Abnormal ER function results in activation of unfolded protein response (UPR) and induction of chaperone genes to alleviate the ER stress. Current studies demonstrate that activation of UPR is associated with biosynthesis of ceramide and sphingosine 1-phosphate (S1P) leading to metabolic regulation. These include pathophysiological conditions such as insulin resistance, atherosclerosis, cardiomyopathy and skin infection. As signaling lipids, ceramide and S1P modulate the degree of cardiovascular events and alleviation of insulin resistance. Recent findings suggest that activation of ER stress leads to modulation of sphingolipid biosynthesis. These bioactive lipids may mediate increased risk of metabolic dysfunction in various tissues. Importantly, elucidation of mechanism regarding sphingolipid regulation by ER stress will provide principal information to development of new therapeutic strategies for systemic metabolic dysregulation and antimicrobial defense in skin. In this review, we focus on the potential roles of ceramide and S1P and mechanisms in these pathophysiological events.