The pathogenesis of drug abuse in patients suffering from drug-induced headache is not known in detail. It is unclear whether drug abuse in chronic daily headache should be classified as a form of drug dependence. Current findings concerning the neurobiological correlates of addictive behavior and affective disorders point to the importance of monoaminergic dysregulation, especially a dysfunction of central serotonergic neurotransmission. We reviewed the literature on drug-induced headache and examined hypothetical pathomechanisms of addiction. Drugs causing drug-induced headache such as paracetamol, coffein and ergotamine interfere with behavior patterns or neurotransmitter systems that are also affected by drugs of abuse. Several drugs that ameliorate acute headache interact with central serotonergic neurotransmission and may affect anxiety and depression in patients with chronic daily headache. Non human primate and human studies revealed mechanisms of serotonergic dysfunction in drug dependence, which may also be relevant for drug-abuse in medication-induced headache. Medication-induced dysfunction of monoaminergic, especially serotonergic neurotransmission, may affect drug dependence by exacerbating mood disorders. Further studies are necessary to assess serotonergic neurotransmission in patients with drug-induced headache and abuse of medication.