The apolipoprotein E4 isoform (apoE4) was initially identified as a susceptibility gene for the development of Alzheimer's disease, and has also recently been associated with poor outcome after acute traumatic and ischemic brain injury. One mechanism by which apoE may influence outcome in acute and chronic neurological disease is by downregulating glial activation and the neuroinflammatory response. Because it does not readily cross the blood-brain barrier (BBB), the apoE holoprotein has limited therapeutic potential. However, smaller peptides derived from the receptor binding region of apoE have been developed that mimic the functional anti-inflammatory and neuroprotective effects of the intact apoE protein. These apoE-derived therapeutic peptides cross the BBB and have been demonstrated to improve functional and histological outcomes in murine models of brain injury. Thus, the development of apoE-derived peptides represent a novel therapeutic strategy for the treatment of acute and chronic neurological disease.