Type-A γ-aminobutyric receptors (GABAARs) are the principal mediators of rapid inhibitory synaptic transmission in the human brain. They are pentameric ligand-gated chloride channels, with a very rich pharmacology, involved in virtually all brain functions. Some of the GABAAR modulators, including benzodiazepines and anaesthetics, are among the most successful drugs in clinical use, and often substances of abuse. Without structural data, the molecular basis for pharmacological modulation of GABAARs remained virtually unknown. I will discuss our path to high resolution structural characterisation of human heteromeric GABAARs and their complexes with multiple small molecule ligands. This work provides unprecedented insights into the mechanisms of GABA-ergic signalling, a reliable structural framework to integrate decades of physiology and pharmacology research and a rational basis for the development of novel GABAAR modulators.