We have developed the first potent, subtype-selective small molecule activator of a G-protein activated inward-rectifying potassium (GIRK) channel. ML297 is potent (EC50 = 160 nM) and as efficacious as activation of GIRK via a Gi/o-coupled receptor (GPCR). ML297 shows a preference for the GIRK1/GIRK2 subunit combination compared to GIRK1/GIRK4 and is inactive on GIRK2/GIRK3 and a number of other potassium channels. This represents a major advance in this field, as the only other known small molecule activators of GIRK channels are simple alcohols and the natural product, naringin, all of which are very low potency and non-selective with respect to GIRK subtype. ML297 possesses favorable physiochemical and dystrophia myotonica protein kinase (DMPK) properties (ML297 is centrally penetrant, affording good CNS exposure in rats), making it a useful tool to selectively probe GIRK1-containing GIRK function in vitro and in vivo which will allow the role of GIRK1-containing GIRKs to be studied in numerous normal and pathophysiological conditions. These properties make ML297 the first and only molecule of its type to selectively probe GIRK1-containing GIRKs and will for the first time allow the potential therapeutic utility of GIRK as a target for numerous important therapeutic indications to be examined.