Migraine is a serious illness with a spontaneous clinical evolution into a chronic form. In some episodic migraines, increase of crises frequency modifies the headache pattern in the chronic form, defined as chronic migraine (CM), with headache frequency of 15 days/month. One-year prevalence of CM includes around 2-4% of the general population. Migraine progression from episodic to chronic form is realized through a period of time involving several months or years, during which an increase of attack frequency occurs. Migraine shows a wide spectrum of comorbidities, including cardiocerebral, vascular, psychiatric, metabolic, neurologic as well as other pathologies. The single/multiple presence of such comorbidities represents a fixed factor in the process of chronicization into CM. Risk factors including medication overuse headache (MOH), obesity, and lifestyle cooperate in the evolution process to CM. MOH is the most severe complication of CM, and similarly to CM its appearance is gradual. Both CM and MOH show particular genetic background able to favor the appearance of chronicity and abuse. Rehabilitation consists of drug withdrawal procedures, re-prophylaxis through administration of innovative drugs, such as OnabotulinumtoxinA and/or topiramate, to avoid relapsing attacks, and behavioral strategies to minimize the role of risk factors. The initial relief step for drug abusers always relies in drug withdrawal. The feasible diagnostic setting for a CM tailored treatment based on the application of pharmacogenomics will allow us to predetermine the efficacy of single old and new drugs by avoiding abuse due to non-responsivity of the acute drug.