The GABA-A receptor system is implicated in a number of neurological diseases, making GABA-A receptor ligands interesting as potential therapeutic agents. Only a few different classes of structures are currently known as ligands for the GABA recognition site on the GABA-A receptor complex, reflecting the very strict structural requirements for GABA-A receptor recognition and activation. Within the series of compounds showing agonist activity at the GABA-A receptor site that have been developed, most of the ligands are structurally derived from the GABA-A agonists muscimol, THIP or isoguvacine. Using recombinant GABA-A receptors, functional selectivity has been shown for a number of compounds such as the GABA-A agonists imidazole-4-acetic acid and THIP, showing highly subunit-dependent potency and maximal response. In the light of the interest in partial GABA-A receptor agonists as potential therapeutics, structure-activity studies of a number of analogues of 4-PIOL, a low-efficacy partial GABA-A agonist, have been performed. In this connection, a series of GABA-A ligands has been developed showing pharmacological profiles from moderately potent low-efficacy partial GABA-A agonist activity to potent and selective antagonist effect. Only little information about direct acting GABA-A receptor agonists in clinical studies is available. Results from clinical studies on the effect of the GABA-A agonist THIP on human sleep pattern shows that the functional consequences of a direct acting agonist are different from those seen after administration of GABA-A receptor modulators.