Introduction: Fingolimod was the first oral disease-modifying treatment approved for relapsing-remitting multiple sclerosis (MS) that serves as a sphingosine-1-phosphate receptor (S1PR) agonist. The efficacy is primarily mediated by S1PR subtype 1 activation, leading to agonist-induced down-modulation of receptor expression and further functional antagonism, blocking the egression of auto-aggressive lymphocytes from the lymph nodes in the peripheral compartment. The role of S1P signaling in the regulation of other pathways in human organisms through different S1PR subtypes has received much attention due to its immune-modulatory function and its significance for the regeneration of the central nervous system. The more selective second-generation S1PR modulators have improved safety and tolerability profiles. Areas covered: This review has been carried out based on current data on S1PR modulators, emphasizing the benefits of recent advances in this emergent class of immunomodulatory treatment for MS. Expert opinion: Ongoing clinical research suggests that S1PR modulators represent an alternative to first-line therapies in selected cases of MS. A better understanding of the relevance of selective S1PR pathways and the ambition to optimize selective modulation has improved the safety and tolerability of S1PR modulators in MS therapy and opened new perspectives for the treatment of other diseases.