The Sphingosine 1-phosphate receptor (S1P-R) signaling system has proven to be of biological and medical importance in autoimmune settings. S1P1-R is a validated drug target for multiple sclerosis (MS) for which FTY720 (Fingolimod), a S1P1,3-5-R pan-agonist, was recently approved as the first orally active drug for the treatment of relapsing-remitting MS. Transient bradycardia and long half-life are the FTY720 critical pitfalls. This review provides the latest advances on next-generation S1P1-R modulators from 2012 up to date, with an overview of the chemical structures, structure-activity relationships, and relevant biological and clinical properties.