Modulation of lymphocyte trafficking, mainly mediated by S1P1, is the main mechanism responsible for the beneficial effects of S1P drugs, such as fingolimod (FTY720), the first nonselective S1P receptor agonist approved for relapsing remitting (RRMS) patients [19,20] and siponimod (BAF312), a S1P1 and S1P5-selective fingolimod-congener, one of the few MS drugs approved for secondary progressive MS (SPMS) [21]. The gene discussed is S1PR5; the disease is secondary progressive multiple sclerosis.