Ligands of the benzodiazepine binding site of the GABA-A receptor come in three flavors: positive allosteric modulators, negative allosteric modulators and antagonists, all of which can bind with high affinity. The GABA-A receptor is a pentameric protein which forms a chloride selective ion channel and ligands of the benzodiazepine binding site stabilize three different conformations of this receptor channel. Classical benzodiazepines exert a positive allosteric effect by increasing the affinity of channel opening by the agonist γ-aminobutyric acid (GABA). We concentrate here on the major adult isoform, the α1β2γ2 GABA-A receptor. The binding pocket for benzodiazepines is located in a subunit cleft between γ2 and α1 subunits in a position homologous to the agonist binding site for GABA that is located between α1 and β2 subunits. It is reviewed here how we arrived at this picture. In particular, point mutations were performed in combination with subsequent analysis of the expressed mutant proteins using either electrophysiological techniques or radioactive ligand binding assays. The predictive power of these methods is assessed by comparing the results with the predictions that can be made on the basis of the recently published crystal structure of the acetylcholine binding protein that shows homology to the N-terminal, extracellular domain of the GABA-A receptor.