Currently available drugs for the acute treatment of migraine, i.e. ergot alkaloids and triptans, are cranial vasoconstrictors. Although cranial vasoconstriction is likely to mediate -at least a part of- their therapeutic effects, this property also causes vascular side-effects. Indeed, the ergot alkaloids and the triptans have been reported to induce myocardial ischemia and stroke, albeit in extremely rare cases, and are contraindicated in patients with known cardiovascular risk factors. In view of these limitations, novel antimigraine drugs devoid of vascular (side) effects are being explored. Currently, calcitonin gene-related peptide (CGRP) receptor antagonists, which do not have direct vasoconstrictor effects, are under clinical development. Other classes of drugs, such as 5-HT(1F) receptor agonists, glutamate receptor antagonists, nitric oxide synthase inhibitors, VPAC/PAC receptor antagonists and gap junction modulators, have also been proposed as potential targets for acute antimigraine drugs. Although these prospective drugs do not directly induce vasoconstriction, they may well induce indirect vascular effects by inhibiting or otherwise modulating the responses to endogenous vasoactive substances. These indirect vascular effects might contribute to the therapeutic efficacy of the above compounds, but may alternatively also lead to vascular side-effects. As described in the current review, some of the prospective antimigraine drugs with a proposed non-vascular mechanism of action may still have direct or indirect vascular effects.