Botulinum toxin, a potent muscle relaxant, has been found to have analgesic effects in patients with various pain syndromes. Both in vitro and in vivo studies showed the ability of the toxin to block the release of pain neurotransmitters, such as substance P, glutamate, and calcitonin gene-related peptide. The effect of the toxin, and specifically of one of its serotypes, botulinum neurotoxin type A, on headaches, has been extensively studied. This serotype is available in the United States in 3 forms, including as onabotulinumtoxinA. Data from clinical trials confirmed the efficacy, safety, and tolerability of onabotulinumtoxinA in the prophylactic treatment of chronic migraine, the most severe and debilitating type of migraine, in adults. The drug was approved by the Food and Drug Administration for this indication in 2010. The drug was not found to be effective for episodic migraine or tension-type headache. Noncontrolled studies suggest the efficacy of the toxin for headache associated with craniocervical dystonia. Proper injection technique and appropriate patient selection are essential for achieving positive results after treatment with onabotulinumtoxinA. The recommended injection paradigm combines a fixed site/fixed dose and follow the pain approaches, with the toxin injected to multiple sites of the head and neck, at a total dose of 155U-195U. The treatment is given at intervals of 12 weeks on average. The efficacy of onabotulinumtoxinA for some headaches, its long duration of action, and its favorable adverse effect profile make it a viable treatment option for the appropriate headache patients. The drug may be particularly suitable for patients who cannot tolerate, or are not compliant with, the daily intake of oral headache preventive drugs.