Publisher Summary This chapter discusses the proposed mechanisms of action of migraine therapy, the various approaches to improve both efficacy and safety, and the future areas of study. Research and development in receptor-based mechanisms for migraine therapy has proceeded at a rapid pace in the recent years. Several new products, based on the improvements of the prototype, sumatriptan, are being introduced into the market. Since the introduction of this drug, the search for safe and effective treatments for migraine pain has accelerated in the pharmaceutical industry. Sumatriptan is developed, using classical pharmacological methodology, employing the contraction of the dog saphenous vein preparation. As modern receptor binding and classical pharmacological methods began to be reconciled, it appeared that there is a relationship between the “5-HT1-like” receptor of the dog saphenous vein and the 5-HT1 D receptor described in the binding studies. Sumatriptan became a selective tool to study 5-HT1D receptors. The advent of molecular cloning further complicated the interpretation of these data because two separate genes encoding 5-HT1D receptors have been discovered, each with high affinity for sumatriptan. Further, in rat and mouse, one of these receptors, 5-HT1Dβ, had a very different pharmacological profile and is known as a separate subtype, 5-HT1B. Whether improvements in the pharmacokinetic parameters or in the degree of the central nervous system (CNS) penetration affect rebound migraine or have a higher degree of efficacy awaits large population studies. Newer agents, acting through neuronal mechanisms, such as 5-HT1D selective or 5-HT1F selective, await efficacy trials in humans.