The human 5-HT1B and 5-HT1D receptors are especially similar in sequence despite being encoded by two distinct genes. Although, human 5-HT1B and 5-HT1D receptors have been pharmacologically differentiated using nonselective 5-HT1B / D receptor antagonists such as ketanserin (1), ritanserin (2) and methiothepin (3), the precise function of these receptors remains undefined, and progress toward this has been hampered by the lack of selective ligands. The interest of the major pharmaceutical companies in 5-HT1B / 1D antagonists increased by the discovery of potent and selective tools, combined with the fact that the blockade of terminal 5-HT1B receptors by selective antagonists has been proposed as a new approach for more efficient and / or fast-acting antidepressant drugs, since the acute blockade of these 5-HT autoreceptors will, in theory, immediately mimic their desensitization. Furthermore, it has been also suggested that supersensitive 5- HT1B / 1D receptors may be involved in the pathophysiology of obsessive compulsive disorders (OCD). In the 5-HT1B / 1D agonist field, since the discovery of sumatriptan (26) (a 5-HT1B / 1D receptor agonist) as an effective treatment for migraine headache, intensive research in this area has led to several second-generation compounds, a few of which have either entered the market place or are in late clinical trials. Beside the antimigraine activity of the 5-HT1B / 1D agonists in clinical evaluation or already on the market, other potential therapeutic evaluations (such as gastric motor effect, bipolar disorder, autism, anti-aggressive effects) with these drugs are being investigated. This article highlights and reviews the research advances published in the 5-HT1B / 1D antagonist and agonist literature. The article is supplemented with selected references on the design, synthesis and development of novel 5-HT1B / 1D agents, and on studies to understand their mechanism and pathophysiology. Emphasis is given to recent advances in the potential therapeutic applications of 5-HT1B / 1D serotonergic agents. By no means has any attempt been made to exhaustively review the literature but rather, primary references along with citations to recent literature reviews have been included in each section.