Changes in neural activity caused by exposure to drugs may trigger homeostatic mechanisms that attempt to restore normal neural excitability. In Drosophila, a single sedation with the anesthetic benzyl alcohol changes the expression of the s/o K+ channel gene and induces rapid drug tolerance. We demonstrate linkage between these two phenomena by using a mutation and a transgene. A mutation that eliminates s/o expression prevents tolerance, whereas expression from an inducible s/o transgene mimics tolerance in naïve animals. The behavioral response to benzyl alcohol can be separated into an initial phase of hyperkinesis and a subsequent phase of sedation. The hyperkinetic phase causes a drop in s/o gene expression and makes animals more sensitive to benzyl alcohol. It is the sedative phase that stimulates s/o gene expression and induces tolerance. We demonstrate that the expression level of s/o is a predictor of drug sensitivity.