Communication between nerve cells depends on the balance between excitatory and inhibitory circuits. GABA, the major inhibitory neurotransmitter, regulates this balance and insufficient GABAergic activity is associated with numerous neuropathological disorders including pain. Of the various GABA receptor subtypes, the δ-containing receptors are particularly interesting drug targets in management of chronic pain. These receptors are pentameric ligand-gated ion channels composed of α, β and δ subunits and can be activated by ambient levels of GABA to generate tonic conductance. However, only a few ligands preferentially targeting δ-containing GABA receptors have so far been identified, limiting both pharmacological understanding and drug-discovery efforts, and more importantly, understanding of how they affect pain pathways. Here, we systemically review and discuss the known drugs and ligands with analgesics potential targeting δ-containing GABA receptors and further integrate the biochemical nature of the receptors with clinical perspectives in pain that might generate interest among researchers and clinical physicians to encourage analgesic discovery efforts leading to more efficient therapies.