In this review, we summarize the biological roles of S1P/ceramide in obesity and insulin signaling and discuss the prospects of S1P receptor (S1PR) agonists for use as therapeutics, partly based on our results [1,2], where obesity and T2DM could be treated by modulating specific S1PR signaling. This evidence concerns the gene MBTPS1 and obesity due to melanocortin 4 receptor deficiency.