The TRAIL death receptor KILLER/DR5 is induced by DNA damaging agents in wild-type p53-expressing cells. Here we show that, unlike the p53-target CDK-inhibitor p21WAF1/CIP1, the TRAIL death receptor KILLER/DR5 is only induced in cells undergoing p53-dependent apoptosis and not cell cycle arrest. Thus GM glioblastoma cells carrying an inducible MMTV-driven p53 gene undergo cell cycle arrest and upregulate p21 but not KILLER/DR5 expression upon dexamethasone exposure. WI38 normal lung fibroblasts undergoing cell cycle arrest in response to ionizing irradiation also induce p21 but not KILLER/DR5 gene expression. KILLER/DR5 upregulation is also deficient in irradiated lymphoblastoid cells derived from patients with Ataxia Teleangiectasia suggesting a role for the ATM-p53 pathway in regulating KILLER/DR5 expression after DNA damage. Inhibition of transcription by Actinomycin D blocks both KILLER/DR5 and p21 induction in cells undergoing p53-dependent apoptosis. Our results suggest that the p53-dependent transcriptional induction of KILLER/DR5 death receptor is restricted to cells undergoing apoptosis and not cells undergoing exclusively p53-dependent G1 arrest.