Modeling of focal cerebral ischemia seeks to understand mechanisms of injury and to test agents as potential stroke therapies. However, modeling has been singularly unpredictable in ischemic cerebrovascular disease for a number of reasons related to the incompletely understood pathophysiology of ischemic stroke and to the characteristics of models prepared to mimic the clinical condition. The development of models of focal cerebral ischemia must take into account known species differences and idiosyncrasies, underlying vascular disease processes, the nature of thrombotic processes, cellular reactivities, the presence of co-stimulation (e.g., inflammation), the characteristics of immunologicals and reporter molecules, the coincident use of other pharmacologic modifiers (e.g., anesthesia), and stress. These elements are also potential contributors to cerebral tissue injury and its assessment but may affect other species differentially. On the other hand, study design issues have been shown to be particularly relevant to limiting development of some agents for clinical stroke treatment. Experience from experimental and clinical work on vascular active approaches (e.g., plasminogen activators) suggests that active dialogue regarding the relationships between clinical outcomes and outcomes in appropriate animal models is necessary. Success appears more likely when the model more closely matches the known human pathophysiology and the interventions applied in the models are definitely characterized in that species. Rather than moving directly to interventional studies in humans, the use of several appropriate animal models is encouraged where those models exist. Where not, careful consideration of study design and the biology of the disorder is a prerequisite.