Testicular germ cell cancers remain one of the few solid tumors routinely cured in advanced stages with conventional cisplatin-based chemotherapy. The mechanisms remain largely unknown. Through use of gene-expression array profiling we define immediate transcriptional targets in response to cisplatin in testicular germ cell-derived human embryonal carcinoma cells. We report 46 genes upregulated and five genes repressed by cisplatin. Several of these gene products, including FAS, TRAILR3, PHLDA3, LRDD, and IER3 are previously implicated in the apoptotic death receptor pathway, while others including SESN1, FDXR, PLK3, and DDIT4 are known mediators of reactive oxygen species generation. Approximately 54% of the upregulated genes are established or suspected downstream targets of p53. Specific siRNA to p53 prevents cisplatin-mediated activation of p53 and p53 pathway genes and renders embryonal carcinoma cells relatively resistant to cisplatin cytotoxicity. Interestingly, in p53 knockdown cells nearly the entire set of identified cisplatin targets fail to respond or have a diminished response to cisplatin, suggesting that many are new direct or indirect targets of p53 including GPR87, STK17A, INPP5D, FLJ11259, and EPS8L2. The data indicate that robust transcriptional activation of p53 is linked to the known hypersensitivity of testicular germ cell tumors to chemotherapy. Many of the gene products may participate in the unique curability of this disease.