Two thirds of patients with medication-overuse headache (MOH) fulfilled criteria for dependence on acute symptomatic treatments for pain, not exclusive of psychoactive medications, based on the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders. Several questionnaires have been used to assess dependent behavior in patients with MOH. Findings regarding underlying psychological profiles of dependence and MOH are not consistent. Nevertheless, several neuroimaging, genetic, and neurobiological studies support the existence of the common pathophysiological features of dependence and MOH and suggest a link between them. This review highlights recent studies on the relationship between dependence and MOH. This issue is important because it implies a treatment strategy in managing patients with MOH by providing the treatment of dependence.