sphingosine 1 phosphate receptor s1pr modulators possess a unique mechanism of action in the treatment of multiple sclerosis ms subtype 1 of the s1pr is expressed on the surface of lymphocytes and is important in regulating egression from lymph nodes the s1pr modulators indirectly antagonize the receptor s function leading to sequestration of lymphocytes in the lymph nodes fingolimod was the first s1pr modulator to receive regulatory approval for relapsing remitting ms after 2 phase iii trials demonstrated potent efficacy safety and tolerability fingolimod can cause undesirable effects as a result of its interaction with other s1pr subtypes which are expressed in diverse tissues including cardiac myocytes as such agents that more selectively target subtype 1 of the s1pr are of interest and are at various stages of development these include ponesimod act128800 siponimod baf312 ozanimod rpc1063 ceralifimod ono 4641 gsk2018682 and mt 1303 data from phase ii trials and early results from phase iii studies have been promising and will be presented in this review of special interest are results from the expand study of siponimod which suggest a potential role for s1pr modulators in secondary progressive ms.