Gene expression profiling of anatomically diverse carcinomas and their corresponding normal tissues was used to identify genes with cancer-associated expression. We show here that the ubiquitin conjugase, UbcH10, is significantly overexpressed in many different types of cancers and is associated with the degree of tumor differentiation in carcinomas of the breast, lung, ovary and bladder, as well as in glioblastomas. We also show that UbcH10 overexpression in gastro-esophageal, and probably other carcinomas may be a direct consequence of chromosomal amplification at the UbcH10 locus, 20q13.1, a region known to be amplified in diverse tumors. To evaluate whether inhibition of UbcH10 function may be therapeutically relevant in cancer, we used small interfering RNAs (siRNAs) to silence UbcH10 transcription selectively. Diminution of UbcH10 expression significantly inhibited both tumor and normal cell proliferation without inducing cell death. However, when combined with agonists of the DR5/TRAIL receptor, siRNAs directed against the UbcH10 transcript dramatically enhanced killing of cancer cells, but not of proliferating primary human epithelial cells or fibroblasts. Together, these data demonstrate that UbcH10 plays an important role in tumor development and that its inhibition in combination with agonists of the TRAIL receptor may provide an enhanced therapeutic index.