GPR17 is an orphan G protein-coupled receptor involved in orchestration of oligodendrocyte differentiation and myelination in the central nervous system. In this issue of Science Signaling, Hennen et al. used a signaling pathway-unbiased screen to identify two small molecule activators of this receptor. One of these, MDL29951, was carried forward to illustrate GPR17-dependent activation of Gαi- and Gαq-promoted signaling pathways in cell lines expressing recombinant GPR17, whereas no effect was observed with previously proposed but dubitable agonists (uracil nucleotides and cysteinyl leukotrienes) of this receptor. Conversely, MDL29951 did not activate any of the known uracil or adenine nucleotide-activated P2Y receptors or cysteinyl leukotriene receptors. Gαi- and Gαq-dependent signaling responses also were observed in primary rat oligodendrocytes in the presence of MDL29951. Moreover, MDL29951 diminished myelination in primary oligodendrocytes isolated from heterozygous mice but had no effect on myelination in oligodendrocytes from GPR17 knockout mice. Effects of a small-molecule GPR17 agonist observed during oligodendrocyte differentiation support the idea that development of antagonists of GPR17 is a rational goal for elaboration of pharmacotherapies in demyelinating diseases.