Although the primary cellular targets of many anticancer agents have been identified, less is known about the processes leading to the selective cell death of cancer cells or the molecular basis of drug resistance. p53deficient mouse embryonic fibrobiasts were used to examine systematically the requirement for~ 53 in cellular sensitivity and resistance to a diverse group of anticancer agents. These results demonstrate that an oncogene, specifically the adenovirus EIA gene, can sensitize fibrobiasts to apoptosis induced by ioniring radiation, L-fluorouracil, etoposide, and adriamytin. Furthermore, the p53 tumor suppressor is required for efficient execution of the death program. These data reinforce the notion that the cytotoxic action of many anticancer agents involves processes subsequent to the interaction between drug and cellular target and indicate that divergent stimuli can activate a common cell death program. Consequently, the involvement of p53 in the apoptotic response suggests a mechanism whereby tumor ceils can acquire crossresistance to anticancer agents.