Medication-overuse headache (MOH) can be viewed as an interaction between the worsening of the primary headache course and individual predispositions for dependence. We present here a review of the clinical and biological data raising the role of dependence-related behavior in MOH. Indeed, several clinical studies show that acute headache medications containing psychoactive components (barbiturates, opiates) are associated with an increased risk of MOH. Diagnostic and Statistical Manual of Mental Disorders, 4th edition substance dependence criteria were identified in a sub-group of MOH patients. Comorbidity between MOH and substance-related disorders has also been showed. Recent neuroimaging, biological, and pharmacogenetic studies suggest the existence of an overlap between the pathophysiological mechanisms of MOH and those of substance-related disorders. These data support the proposition of separating 2 sets of MOH patients: the first one in which the illness is mainly due to the worsening of the headache course, and the second one in which behavioral issues are a major determinant of the illness. Detection of a psychological dependence component in a sub-group of MOH patients should have direct relevance to disease management.