The discovery and development of the 5-HT1810 agonist sumatriptan for alleviating migraine pain has been an important advance in the field of modern headache treatment and research. This important therapeutic advance is not without it's shortcomings. When administered orally, it is poorly absorbed with clinically relevant headache relief occurring at least two hours after drug administration. Due to its agonist action at peripherovascular 5-HT1D-Iike receptors, it is contraindicated in patients with coronary artery disease. Furthermore, headache recurs within a 24 hour period in 40% of patients treated. Given the large unmet medical need, market size and sumatriptan's shortcomings, a number of second-generation agents have been developed which are structurally and pharmacologically similar to sumatriptan, but have improved oral pharmacokinetic profiles. These include zolmitriptan, naratriptan, rizatriptan, avitriptan, alniditan, eletriptan and BMS-181885, all of which have been shown to be clinically effective. In this review, the SAR of the second-generation triptans at the 5-HT 18 and 5-HT10 receptors as well as distinct pharmacological actions in novel animal models are discussed.