Ergotamine has historically been used to treat migraine since the middle ages, and as a pharmaceutical since 1926,1 but is limited by poor tolerability (nausea, vomiting, and cardiovascular effects), thus attempts were made to synthesize compounds with the same efficacy but reduced safety concerns. Dihydroergotamine (DHE) was synthesized by Stoll and Hofmann in 1943 and was the 45th experimental modification hence the original intravenous (IV) formulation was branded as D.H.E. 45®. This modified molecule is more potent than ergotamine as an alpha?adrenergic antagonist (but less potent as an arterial vasoconstrictor), from which it is derived and causes less nausea and vomiting.2 DHE was originally envisaged as an antihypertensive agent, but it was later shown to be highly effective in treating migraine at the Mayo Clinic.3 DHE has a chemical structure similar to many naturally occurring neurotransmitters (eg, epinephrine, norepinephrine, dopamine, and serotonin) and as a result binds to a broad range of receptors (Fig. 1).4 DHE was approved in 1946 as one of the first drugs of the post?World War II era and continues to be a choice today for acute migraine, status migrainosus, and cluster headaches. DHE is erratically absorbed through the gut with absorption ranging from 10 to 60% and extremely poor oral bioavailability (0.07?0.14%),5 and therefore this molecule is limited to non?oral routes of administration. IV administration of DHE is especially effective for treating acute migraine and has a high response rate. Other routes of administration such as nasal delivery (Migranal) have been approved but report 32% bioavailability6 and variable pharmacokinetics (PK) that create therapeutic challenges (eg, unpredictable clinical response or adverse events). Thus, an unmet need exists for more effective and consistent delivery of DHE that provides improved safety, tolerability, and ease of use while retaining its efficacy. In the last decade, an orally inhaled version of DHE (suspended in hydrofluoroalkane [HFA] propellant), MAP0004 showed promise with a successful clinical development program but failed to overcome manufacturing issues so has never been approved. Now, with renewed interest in the disease, at least 3 companies are developing nasally delivered options of DHE while other non?oral, non?injected products are also in development.