In recent years, research implicating biochemical abnormalities in various pathological conditions has spiraled. Headache is an area in which numerous research studies have been conducted examining biochemical alterations. We have noticed several similarities in biochemical changes reported to occur in migraine and in experimental traumatic brain injury. The most common symptom in mild head injury or mild traumatic brain injury is headache which, in many instances, resembles migraine but has a poorly understood pathophysiology. Biochemical mechanisms believed to be similar in both conditions include: increased extracellular potassium and intracellular sodium, calcium, and chloride; excessive release of excitatory amino acids; alterations in serotonin; abnormalities in catecholamines and endogenous opioids; decline in magnesium levels and increase in intracellular calcium; impaired glucose utilization; abnormalities in nitric oxide formation and function; and alterations in neuropeptides. In this paper, these preposed biochemical alterations will be reviewed and compared. Very similar alterations suggest posttraumatic headache associated with mild head injury and migraine may share a common headache pathway.