Drug-induced headache is one of the important causes of poor compliance. Drug-induced headache can be diagnosed by withdrawal of suspected agents and plausible relationship. The drugs most likely reported to be associated with headache are nitric oxide donors, phosphodiesterase inhibitors, lithium, and tetracycline and suggested mechanisms are vasodilatation, increased intracranial pressure, and aseptic meningitis. Some patients are more susceptible to drug-induced headache. Drug-induced headache can be controlled by reducing dose, discontinuation of the drug, and symptomatic medications, if needed. Consideration about previous headache history is recommended in randomized drug trial and starting new drug.