Following focal cerebral ischemia (“stroke”) a complex and dynamic interaction of vascular cells, glial cells, and neurons determines the extent of the ensuing lesion. Traditionally, the focus has been on mechanisms of damage, while recently it has become clear that endogenous mechanisms of protection are equally important for the final outcome. Glial cells, in particular astrocytes, have always been viewed as supporters of neuronal function. Only recently a very active role for glial cells has been emerging in physiology and pathophysiology. Not surprisingly, then, specific protective pathways have been identified by which these cells can protect or even help to regenerate brain tissue after acute insults. However, as exemplified by the existence of the glial scar, which forms around lesioned brain tissue, is composed mainly of astrocytes and plays a key role in regeneration failure, it is an oversimplification to assign merely protective functions to astrocytes. The present review will discuss the role of astrocytes in ischemic brain injury with a focus on neuroprotection in general. In this context we will consider particularly the phenomenon of “ischemic tolerance,” which is an experimental paradigm helpful in discriminating destructive from protective mechanisms after cerebral ischemia. © 2005 Wiley‐Liss, Inc.