Although the exact cascade of events that culminate into a migraine attack remains elusive, the mechanisms that underlie the manifestation of migraine pain have been better studied, and results obtained in animal models provide insight into the human situation. In this respect, primary headaches such as migraine and cluster headaches are best described as "the manifestation of a hereditary or predisposed sensitivity of neurovascular reactions to certain stimuli or to cyclic changes in the central nervous system". Evidence indicates that a migraine originates in the brain and, in its process and evolution, affects the meningeal blood vessels and leads to the development of head pain. This manifestation has been related to the activation of the trigeminovascular sensory nerves, which release neuropeptides that mediate vasodilation, and the proinflammatory reaction thought to be involved in pain generation and transmission. Such a concept underscores the fact that the relationship between the nerves and the blood vessels is of paramount importance in the manifestation of the disease's symptoms. Multiple characteristics in migraine sufferers, including recently identified genetic factors, may determine their thresholds to various neuronal and/or vascular stimuli and as such may form the basis for the future understanding of migraine pathogenesis.