Leak potassium currents in the nervous system are often carried through two-pore-domain potassium (K2P) channels. These channels are regulated by a number of different G protein-coupled receptor (GPCR) pathways. The TASK subfamily of K2P channels are inhibited following activation of the G protein Galpha(q). The mechanism(s) that transduce this inhibition have yet to be established but there is evidence to support a role of phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis products, depletion of PIP2 itself from the membrane, or a direct action of activated Galpha(q) on TASK channels. It seems possible that more than one pathway may act in parallel to transduce inhibition. By contrast, TRESK channels are stimulated following activation of Galpha(q). This is due to stimulation of the protein phosphatase, calcineurin, which dephosphorylates TRESK channels and enhances their activity. TREK channels are the most widely regulated of the K2P channel subfamilies being inhibited following activation of Galpha(q) and Galpha(s) but enhanced following activation of Galpha(i). The multiple pathways activated and the apparent promiscuous coupling of at least some K2P channel types to different G protein regulatory pathways suggests that the excitability of neurons that express K2P channels will be profoundly sensitive to variations in GPCR activity.