The proto-oncogene bcl-2 plays a key role in regulating programmed cell death in neurons. The present review discusses the mechanisms by which bcl-2 family genes regulate programmed cell death, and their role in controlling cell death in cerebral ischemia and traumatic brain. Expression of several bcl-2 family members is altered in brain tissues after ischemia and trauma, suggesting that bcl-2 family genes could play a role in determining the fate of injured neurons. Furthermore, alteration of expression of bcl-2 family genes using transgenic approaches, viral vectors, or anti-sense oligonucleotides modifies neuronal cell death and neurological outcome after injury. These data suggest that the activity of bcl-2 family gene products participates in determining cellular and neurologic outcomes in ischemia and trauma. Strategies that either mimic the death-suppressor effects or inhibit the death-promoter effects of bcl-2 family gene products may improve outcome after ischemia and trauma.