The shift in our understanding of migraine as a vascular disorder to a brain disorder has opened new avenues for the development of novel therapeutics with neural targets. The advent of 5-HT1B/1D receptor agonists, the triptans, in the 1990s was a crucial step in the modern evolution of treatment. The use of triptans, like their predecessors, is limited by their vasoconstrictor effects, and new development has been slowed by poor academic research funding to identify new targets. The development of agents without vascular effects, such as calcitonin gene-related peptide receptor antagonists and selective serotonin 5-HT1F receptor agonists, will bring more effective treatments to a population currently without migraine-specific options. In addition, advances in understanding migraine pathophysiology have identified new potential pharmacologic targets such as acid-sensing ion channels, glutamate and orexin receptors, nitric oxide synthase (NOS), and transient receptor potential (TRP) channels. Although previous attempts to block subtypes of glutamate receptors, NOS, and TRP channels have had mixed outcomes, new molecules for the same targets are currently under investigation. Finally, an entirely new approach to migraine treatment with noninvasive neuromodulation via transcutaneous neurostimulation or transcranial magnetic stimulation is just beginning. Hopefully in the coming years we will see a new era of migraine therapy, with multiple classes of better-tolerated, more effective agents targeting diverse yet specific migraine mechanisms.