There are numerous ways by which the middle cerebral artery (MCA) can be occluded in order to provoke a focal cerebral ischemia (either of a permanent nature or with reperfusion) in experimental animals: electrocoagulation, microvascular clips, sutures or intraluminal thread models – that include both an extravascular and endovascular approach, respectively –, injection of a foreign or autologous thrombus, microemboli, the production of an in situ clot formation by using rose-Bengal, or even the placement of a balloon catheter around, or directly into, the MCA per se. Some of these models were specifically designed to establish a reproducible volume of ischemic damage in which various pharmacological agents could be screened for their efficacy as “neuroprotector agents” in as small a number of animals as possible without losing statistical pertinence. None of the widely tested “neuroprotector agents” employed in any of the above models of focal cerebral ischemia has found a place in the clinical treatment of stroke. This finding is perhaps not surprising, as stroke in humans is rarely confined to one anatomical brain region, is often associated with other underlying pathologies, such as hypertension or diabetes, and where the location of the ischemic damage may be more important, in terms of neurological deficits, than the actual volume of the infarct itself. In this chapter, we describe two experimental models of stroke which, we believe, represent more closely the clinical condition of a cerebrovascular accident. The first model, one of thromboembolic cerebral ischemia in the rat, was established more than 20 years ago by Longa et al. (see 12 ). The procedure involves the injection of an autologous blood clot into the internal carotid artery (ICA) of the anesthetized rat which then, due to the size of the clot, becomes lodged at the origin of the MCA. However, there are a number of disadvantages associated with this model including: a high mortality rate after periods of ischemia >45 min; secondary ischemic foci following disruption of the clot (if treated by thrombolysis); variability in the final location of the clot and irregularity of the final infarct volume as a consequence of the degree of reduction in cerebral blood flow (CBF) to the brain region in question. Nonetheless, these “so-called” disadvantages are indeed encountered in humans following stroke. The second method is more recent and also involves the establishment of a thromboembolic stroke, this time in the anesthetized mouse. This new experimental model was developed by Orset et al. (see 13 ). To induce a focal cerebral ischemia, a micropipette is used to deliver a given volume of thrombin directly into the lumen of the exposed MCA, thereby obstructing the blood supply to the MCA territory as can be determined by Laser Doppler sonography. Given the limited vascular supply in this lissencephalic species, the infarcts are highly reproducible and there is no mortality associated with the surgical intervention. A craniotomy is, however, necessary for this procedure which, in turn, may reduce the additional deleterious consequences of raised intracranial pressure (ICP) normally associated with cerebral ischemia and thus limits the final infarct volume due to the occlusion. The experimental procedures for both the techniques as well as their advantages and disadvantages are described in the following pages.