Heteromeric metabotropic γ-aminobutyric acid_B (GABA_B) receptors for the inhibitory neurotransmitter GABA belong to the family 3 of G-protein-coupled receptors, together with metabotropic glutamate receptors, extracellular Ca²⁺-sensing receptors and some pheromone and taste receptors. It is now generally appreciated that allosteric modulators provide a new perspective for the development of subtype-selective agents acting at G-protein-coupled receptors. Such modulators interact with allosteric binding sites quite separate from the highly conserved agonist binding region, providing a variety of potential modulatory actions. Allosteric interaction modifies the binding affinity of the agonist, and is a commonly found mechanism governing receptor function. The GABA_B receptor itself is unique, as its function depends on heterodimerization of two subunits, GABA_B1 and GABA_B2. Only GABA_B1 has the orthosteric binding region, whereas  GABA_B2 does not bind agonists or antagonists, but is modulatory for GABA_B1. GABA_B2 is also the signaling subunit for G-protein activation; yet no agonist is known. We have found a range of arylalkylamines and unnatural amino-acids that are effective positive modulators of GABA_B receptors. These new modulators proposed at GABA_B receptors may well have novel applications in GABA_B receptor pharmacology.