In most neurons and other excitable cells, calcium-activated potassium channels of small (SK) and large conductance (BK; MaxiK) control excitability and neurotransmitter release. The spontaneous activity of dopamine neurons of the ventral tegmental area is increased by ethanol. This ethanol excitation is potentiated by selective blockade of SK, indicating that SK channels modulate ethanol stimulation of neurons that are critical in reward and reinforcement. On the other hand, ethanol directly modulates BK channel activity in a variety of systems, including rat neurohypophysial nerve endings, primary sensory dorsal root ganglia, nucleus accumbens neurons, Caenorhabditis elegans type-IV dopaminergic CEP neurons, and nonneuronal preparations, such as rat pituitary cells, cerebrovascular myocytes and human umbilical vein endothelial cells. Ethanol action on BK channels can modify neuropeptide and growth hormone release, nociception, cerebrovascular tone, and endothelial proliferation. Ethanol modulates BK channels even when the drug is evaluated using recombinant BK channel-forming alpha (slo) subunits or channel reconstitution in artificial, binary lipid bilayers, indicating that the slo subunit and its immediate lipid microenvironment are the essential targets of ethanol. Consistent with this, single amino acid slo channel mutants display altered ethanol sensitivity. Furthermore, C. elegans slo1 null mutants are resistant to ethanol-induced motor incoordination. On the other hand, Drosophila melanogaster slo null mutants fail to acquire acute tolerance to ethanol sedation. Ethanol action on slo channels, however, may be tuned by a variety of factors, including posttranslational modification of slo subunits, coexpression of channel accessory subunits, and the lipid microenvironment, resulting in increase, refractoriness, or even decrease in channel activity. In brief, both SK and BK channels are important targets of ethanol throughout the body, and interference with ethanol effects on these channels could form the basis for novel pharmacotherapies to ameliorate the actions or consequences of alcohol abuse.