Background or ‘leak’ potassium currents contribute to establishing membrane potential and input resistance in central neurons, and thereby to determining intrinsic neuronal excitability. It is now clear that the so-called two-pore-domain K+ (K2P) channels have the requisite functional properties and neuronal distribution to account for native neuronal background K+ currents (Goldstein et al. 2001). Moreover, K2P channels appear richly endowed with modulatory potential, as dynamic changes in channel activity can be evoked by physicochemical factors, bioactive lipids, anesthetic compounds and neurotransmitters (Goldstein et al. 2001). In this talk, I will discuss our work on identification of native neuronal correlates of K2P channels and on molecular mechanisms by which they are modulated. We used in situ hybridization to describe a differential distribution of multiple K2P channels in the central nervous system, suggesting that distinct subsets of K2P channels contribute to background K+ currents in different types of neurons. The pH-sensitive TASK-1 (K2P3) and TASK-3 (K2P9) channels are widely distributed in the brain, with overlapping and particularly prominent expression in cholinergic and aminergic neurons (Bayliss et al., 2003). We have recorded from these neurons in brain slice preparations and isolated native currents that have properties essentially identical to those of cloned TASK channels, in either homomeric or heteromeric configurations (Bayliss et al. 2003; Berg et al. 2004). For some cell types (i.e. motoneurons), we have used recently available knockout mice to verify that native background K+ currents are indeed due to TASK channels (unpublished). In heterologous expression systems and neurons, TASK channels are activated by inhalation anesthetics and inhibited by neurotransmitters that signal via Gαq-linked receptors. By using channel mutagenesis, we found that up- and down-modulation by anesthetics and neurotransmitters involves a shared channel determinant that includes a conserved domain at the membrane-cytoplasmic interface of the C terminus (Talley & Bayliss, 2002). In terms of signaling pathways interposed between Gαq-linked receptors and TASK channels, we manipulated G protein expression and membrane PIP2 levels in intact and cell-free systems to provide electrophysiological and biochemical evidence that TASK channel inhibition proceeds via a mechanism that is independent of phospholipase C (PLC), the typical effector for Gαq, and instead involves close association of activated Gαq subunits with the channels (Chen et al. 2006). Overall, this work demonstrates the importance of TASK-1 and TASK-3 channel subunits to neuronal background K+ currents and describes novel mechanisms by which these channels are regulated to control neuronal excitability.