Migraine is a common, disabling, neurovascular disorder characterized by episodic attacks of head pain and associated disability plus systemic autonomic and neurologic symptoms. The advent of the triptan class of medication in the 1990s revolutionized the acute treatment of migraine, but many migraineurs do not respond optimally or at all to triptans, have intolerable adverse effects, or have contraindications to their use. Preventive pharmacotherapy has advanced mostly through serendipity, with new drugs being found effective while being used for other indications. There remains a significant need for new medications and devices that can provide effective, rapid, and sustained pain relief without adverse effects or recurrence. Several new acute and preventive therapies for the treatment of migraine and cluster headaches have shown promise and are currently under investigation. This article covers innovative delivery mechanisms, calcitonin gene-related peptide receptor antagonists, antibodies to calcitonin gene-related peptide and its receptor, 5-HT1F receptor agonists, transient receptor potential vanilloid receptor modulators, orexin receptor antagonists, glial cell modulators, and neurostimulation.