Stroke is the second leading cause of death worldwide, and its incidence is expected to rise with the projected increase in the number of aging population. Disturbances of brain iron homeostasis have been linked to acute neuronal injury following cerebral ischemia. Free iron catalyzes the conversion of superoxide and hydrogen peroxide into hydroxyl radicals, which promote oxidative stress leading to subsequent cell death/apoptosis. In recent years, considerable evidence has emerged regarding the role of iron neurotoxicity following experimental cerebral ischemia. Few clinical studies have also attempted to investigate the role of iron in stroke patients. The present review will examine the currently available evidence for iron-mediated neurotoxicity and the potential mechanisms underlying deregulation of iron homeostasis in the brain following cerebral ischemia. Understanding the changes in brain iron metabolism and its relationship to neuronal injury in ischemic stroke could provide new therapeutic targets to improve the outcome of stroke patients.