In this article, we review the use of stably transfected cells to study the regulation of receptor structure and function by chronic drug treatments and compare results from these cells to results obtained from other systems, including neuronal cultures and intact animals. We focus on the γ-aminobutyric acid type A (GABA_A) receptor complex. Sedative/hypnotic drugs such as benzodiazepines, barbiturates and alcohol that potentiate GABA_A receptor function produce tolerance and dependence. Chronic treatment of GABA_A receptor preparations from brain and neuronal cultures with GABA_A agonists, as well as these other three classes of drugs, results in regulation of several properties of the receptor. Drug treatments may regulate levels of binding sites, allosteric binding interactions, receptor function, levels of receptor subunit mRNA and levels of receptor subunit protein. Some or all of these effects may comprise the molecular mechanisms of tolerance to these GABA_A-modulatory drugs. The use of cells stably transfected with neurotransmitter receptors provides a homogeneous population that can be cultured under controlled conditions. As most preparations contain mixed populations of GABA_A receptor subunits, stably transfected cells offer the advantage of the expression of receptors with a defined subunit composition. We conclude that chronic drug treatments regulate allosteric coupling and function of GABA_A receptors in stably transfected cells. This regulation does not appear to be due to decreases in the expression of α1- or β1-receptor subunits or to expression of subunits other than α1, β1, γ2L. Therefore, it is unlikely to be due to changes in receptor subunit composition and probably represents post-translational changes. The rapid regulation of allosteric coupling and function by drug treatment of the stably transfected cells should provide insights to the mechanisms of coupling between GABA_A and benzodiazepine receptors as well as tolerance and dependence of benzodiazepines and ethanol.