No new preventive drugs specific to migraine have appeared for the last 20 years and existing acute therapies need improvement. Unfortunately, no animal models can predict the efficacy of new therapies for migraine. Because migraine attacks are fully reversible and can be aborted by therapy, the headache- or migraine-provoking property of naturally occurring signalling molecules can be tested in a human model. This model has predicted efficacy of nitric oxide synthase inhibition and calcitonin gene-related peptide receptor blockade. The pharmaceutical industry should pay more attention to human models, although methods are different from normal target validation.