It is difficult to attribute the diagnosis of adverse drug reaction to a condition which is also a common symptom. The decision might be arduous in the case of headache, because this disorder is very frequent in the general population. The drugs that more frequently induce headache belong to a variety of therapeutic classes with different mechanisms of action and different toxicity. In the majority of cases the headache has not a typical feature, it is dosedependent, and is associated to other symptoms of neurotoxicity. Some drugs cause, instead, a specific headache: this is the case of NO donors, which are also used in experimental studies in order to induce headache. This review describes the classes of drugs which induce headache, analyzes the frequency of headache induction among the drugs of the same class, and discusses the possible mechanisms underlying headache induction. It is to be hoped that a better awareness of this issue would help the physician to consider it in the differential diagnosis of a recent-onset or changed headache and to avoid prescription of drugs known to cause headache to patients already suffering from this disorder.