The application of Botulinum toxin for several pathological conditions has been largely debated in the last decades and its use has been definitively consolidated for disorders related to increased muscle tone and hyperidrosis. Botulinum neurotoxin (BoNT-A) is a potent toxin produced by an anaerobic bacterium, Clostridium botulinum, which presents several pharmacological proprieties, but also different and serious contraindications. As chronic migraine (CM) is commonly reported as a serious and debilitating condition and a big challenge from the therapeutic point of view, in the last decades, after isolated observations, BoNT-A has been applied as preventive treatment for CM patients and, after randomized and rigorous studies, it has been accepted among the most effective pharmacological treatments for these problematic patients. In the present report, a group of patients suffering from CM with medication overuse was treated with BoNT-A to verify its efficacy for CM. The results confirmed the efficacy of BoNT-A when used at the dosage of 155 UI, according with the PREEMPT study protocol. Although these results are preliminary, in a limited group of patients, they led to intense efforts to enforce the use of BoNT-A for CM and to assess its clinical applicability.