Identification of substances that may cause or trigger headache is important to start effective treatment early to prevent unnecessary suffering, deterioration in quality of life, and the development of chronic pain. Treatment in case of medication overuse and other chronic headache should be decisive and effective. Drug withdrawal and introduction of effective prophylactic medication for the underlying headache disorder should be the primary treatment strategy. Typical headache-inducing substances are nitric oxide, phosphodiesterase, cocaine, alcohol, histamine, carbon oxide, and calcitonin gene-related peptide. The withdrawal of caffeine, estrogen, and opioids is most often associated with the development of headache.