Tremendous progress has been made in the past decades for the treatment of headache disorders. Chronic migraine is the most disabling type of headache and requires the use of acute and preventive medications, many of which are associated with adverse events that limit patient adherence. Botulinum toxin (BoNT) serotype A, a neurotoxin derived from certain strains of Clostridium, disrupts neuropeptide secretion and receptor translocation related to trigeminal nociception, thereby preventing pain sensitization through peripheral and possibly central mechanisms. Ever since the first randomized controlled trial on onabotulinumtoxinA (onabotA) for migraine was published two decades ago, onabotA has been the only BoNT formulation approved for use in the prevention of chronic migraine. Superior tolerability and efficacy have been demonstrated on multiple migraine endpoints in many controlled trials and real-life studies. OnabotA is a safe and efficacious treatment for chronic migraine and possibly high-frequency episodic migraine. Further research is still needed to understand its mechanism of action to fully develop its therapeutic potential.