Cluster headache patients seem to use more licit and illicit substances than the general population. The epidemiologic data supporting this is growing. We included the licit drugs in this review because their use seems to be driven by the same addiction mechanisms leading to illicit drug abuse. Some drugs may be used in an attempt to treat cluster headache, especially cocaine and hallucinogens. Drug exposure may also play a role in CH pathophysiology, as suggested by interesting data on tobacco use and second-hand smoke exposure. A common factor may contribute both to CH and drug use predisposition. Genetic factors may be at play, and the dopaminergic and orexinergic pathways could be targeted for future studies.