Dysfunction of the gamma amino butyric acid (GABA)-ergic system has been purported to play a role in psychiatric disorders, including anxiety and major depression. A clear link between GABA(A) receptors and anxiety has long been established. However, despite the GABA system being the prominent inhibitory neurotransmitter in the brain, a role in depression has been less well validated. GABA(B) receptors, first characterized by Bowery and colleagues 30 years ago, have been long postulated to be involved in the etiology of depression, but a lack of selective, orally active, pharmacological compounds slowed down their assessment. From the mid-1990s, more selective pharmacological and genetic tools for examining the GABA(B) system have provided greater insight into their role in complex behavioral and molecular characteristics. The resulting literature garnered from recent behavioral studies employing selective GABA(B) receptor antagonists and knockout mice suggests in the main that the blockade, or loss of function, of GABA(B) receptors causes an antidepressant-like phenotype. The GABA(B) receptor system has been shown to have substantial interactions with the serotonergic system and neurotrophic factors, such as BDNF. We argue that the potential antidepressant properties of GABA(B) receptor antagonists may be, at least in part, mediated via these interactions. Clinical studies have repeatedly reported alterations in GABA levels, particularly in cortical areas, but studies to specifically assess GABA(B) receptors are lacking. Those available have documented differential gene expression of the GABA(B(2)) subunit but require replication. Therefore, while further research is necessary, it is suggested that GABA(B) receptor antagonists may represent a new class of antidepressant compounds.