Matrix metalloproteinases (MMPs) are involved in the pathogenesis of several diseases of the CNS, that share common pathophysiological processes, such as blood-brain barrier (BBB) disruption, oxidative stress, remodeling of the extracellular matrix (ECM) and inflammation. In ischemic brain injury, MMPs are implicated in various stages of the disease. Early after the onset of ischemia, MMPs contribute to the disruption of the BBB leading to vasogenic edema and to the influx of leucocytes into the CNS. The ability of MMPs to digest the basal lamina of capillaries increases the risk of hemorrhagic transformation of the ischemic tissue. During the acute ischemic phase, maintenance of the ECM is essential for neuronal survival. However, ECM degradation and its reconstitution are critical to tissue recovery. MMPs as a key modulator of ECM homeostasis play a role in the cascades leading to neuronal cell death and tissue regeneration. This pleiotropic implication of MMPs in brain injury has open new areas of investigation, which should lead to innovative therapeutic strategies. Yet MMPs may have a detrimental or beneficial role depending on the stage of brain injury. Simple therapeutic strategies based on MMP inhibition have thus little chance to favorably alter prognosis.