The Cys-loop ligand-gated ion channel (LGIC) family comprises a group of membrane ion channel receptors that play a crucial role in fast synaptic neurotransmission in the central and peripheral nervous system. The members of this superfamily include gamma-aminobutyric acid type A (GABA(A)), neuronal nicotinic acetylcholine (nACh), 5-HT(3), and glycine receptors. These receptors serve as therapeutic sites for general anesthetic, antipsychoactive, antinociceptive, and anxiolytic drugs in the brain. These receptors are also thought to be primary targets of alcohol and other drugs of abuses. A number of studies reported that fatty acids affected the function of GABA(A) receptors in the early nineties. Accumulating evidence has suggested that the derivatives of arachidonic acid (AA), such as anandamide (N-arachidonoylethanolamine, AEA) and arachidonoylglycerol (2-AG), can critically regulate the other members of the Cys-loop LGIC superfamily through a cannabinoid receptor-independent mechanism. This chapter focuses on the results of recent studies showing that the Cys-loop LGICs could be additional molecular targets for fatty acid and endocannabinoid action in the central and peripheral nervous system. Some of these targets may mediate behavioral effects for cannabinoids to alter neuronal function.