Nature provides science and society with a virtually unlimited supply of structurally diverse and biologically active molecules; the natural products. While some are directly useful in commercial applications, others are valuable for studying and understanding biological phenomena at the molecular level. An example is the signaling of nerve cells, which has been explored in considerable detail using a number of bioactive natural products. This review concerns primarily a part of the GABA inhibitory system of the central nervous system, the GABA(A) receptors, and natural products that have been reported to affect GABA(A) receptors in various ways. As the major inhibitory neurotransmittor, GABA plays a central role in the function of the central nervous system and modulates the activities of all neurons. Malfunctions in the GABA-operated systems cause a number of severe mental disorders, which consequently, at least in theory, can be treated with drugs. The natural products discussed in this review, acting on the GABA(A) receptors, are divided into the three main classes; terpenoids, polyacetylenic alcohols, and flavonoids. In addition, in a second part of the review, it is exemplified how knowledge about quantitative structure-activity relationships for a molecular target can be used to design novel, potent and selective compounds targeting the benzodiazepine binding site of the GABA(A) receptors.