The concept of the ischemic penumbra is an important one for both basic investigators of cerebral ischemia and for clinicians who treat stroke patients. The ischemic penumbra has been defined in a variety of ways, but the most clinically relevant definition is that portion of the ischemic territory that is still potentially salvageable, if an appropriate treatment is given. Currently, three main challenges persist for those interested in the ischemic penumbra concept: how can this ischemic region be most accurately identified in stroke patients, what mechanisms of ischemic cell death are most important for progression from penumbra towards irreversible injury and what therapeutic modalities are most likely to impede the development of infarction? Much important information regarding each of these topics has become available recently and will be the focus of this paper.