Modulation of sphingosine 1-phosphate (S1P) signaling represents a solid opportunity for multiple sclerosis (MS) treatment. In this issue, a team at Novartis reports on the identification of the first direct S1P lyase (S1PL) inhibitors as new MS agents. One of the most potent inhibitors reported in their work was demonstrated to be orally bioavailable and fully protective in a MS disease animal model. This work represents an outstanding example of a drug discovery campaign that started with the target identification and validation and culminated with the preclinical tests on animal disease models.