Apoptotic cell death is coordinated by the caspase proteases, and these are activated via two major pathways. One of these depends upon the binding of death receptors, such as Fas (CD95) by their ligands. Alternatively, apoptosis can proceed by the activation of pro-apoptotic Bcl-2 family proteins that induce a permeabilization of the mitochondrial outer membrane, releasing proteins from the intermembrane space. Cytochrome c then triggers caspase activation. In either case, activated “executioner” caspases cleave key substrates within the cell that then cause the apoptotic death. Not all of these key substrates are known. Cellular stress can engage either or both of these pathways to cause apoptosis. DNA damage, heat shock, and other stressors induce expression of Fas-ligand (FasL) on several different cell types, and can sensitize cells to death by ligation of Fas. Dissection of the FasL promoter reveals a number of novel regulatory features consistent with such stress-induced expression. For example, both AP-1 and NF-κB are activated following DNA damage, and this activation is required for induction of FasL expression via binding of these transcription factors to their sites in the FasL promoter. In addition, the promoter appears to be regulated by c-Myc/Max heterodimers, suggesting a link to activation of this important proto-oncogene. We have identified a noncanonical Myc/Max binding site within the FasL promoter that appears to be responsible for this effect. We confirmed that this is indeed a Myc-responsive element by transplanting this site to the promoter for ornithine decarboxylase, replacing its canonical cMyc-binding sites. The chimeric promoter became much more responsive to c-Myc than even the original ODC promoter. Conversely, mutation of the c-Myc site in the FasL promoter destroys its responsiveness to c-Myc or to other activating signals. Therefore, c-Myc is likely to be an important component of FasL expression. When FasL is expressed, it engages Fas on either the same or a neighboring cell. This can include infiltrating inflammatory cells, and the FasL may serve to protect the tissue from inflammatory damage. Upon ligation of Fas, caspases are activated and the cell dies.