The enhancement of GABA-mediated synaptic transmission underlies the pharmacotherapy of various neurological diseases. GABAA receptors are thus targets for neuroactive drugs, including classical benzodiazepines, mediating their anxiolytic, hypnotic and anticonvulsant effects via the benzodiazepine site (BZS). Based on findings that low intrinsic efficacy and subtype selectivity can greatly improve the specificity of drugs targeting the BZS, recent research has identified possible drug leads with apparently little side effects. In particular, drug leads of natural sources have been identified as promising candidates. This review describes the advances in the design of effective therapeutics targeting the GABAA receptor, focusing on the more recent research on naturally occurring drug leads. This includes discussion on the isolation of neuroactive alkaloids and flavonoids from herbal medicines and their rational development based on structure-activity relationships studies. Interest in the development of effective therapeutics from natural sources is clear and awaits to be seen whether their medicinal potential can be fulfilled.