Cancer results in hundreds of thousands of deaths each year worldwide. One underlying cause of cancer is aberrant transcriptional regulation. Targeting the already "unhealthy" state of transcription in cancer cells is likely to cause cancer cell death. However, since all cells require transcription, targeting transcription may affect both cancerous and non-cancerous cells. Furthermore, direct targeting of the core transcription machinery has yet to be established. To provide evidence that transcription can be targeted for cancer therapy, small interfering RNAs (siRNAs) were employed to knockdown core factors associated with RNA Polymerase II (RNAP), the enzyme required for synthesis of all mRNA in eukaryotic cells.;Results show that by targeting chromatin remodeling (BAF170), transcription initiation (Gdown1), and transcription elongation (p-TEFb and TFIIS), inhibition of cancer cell growth can be achieved in breast, prostate, lung, and pancreatic cancer cells in culture. Of the targets examined, TFIIS presented itself as the most suitable for detailed study. In MCF7 cells, targeting TFIIS with siRNA reduces TFIIS mRNA and protein levels, resulting in programmed breast cancer cell death. The non-cancerous breast cell line MCF10A was less affected. Lung, pancreatic and prostate cancer cells also displayed reduced cell proliferation in response to TFIIS siRNA. TFIIS knockdown increased c-Myc and p53 expression in MCF7 cells, but not in MCF10A cells. Microarray results suggest that the affects of TFIIS knockdown are likely to be the result of altered gene expression caused by the reduction in TFIIS. Although transcription is a fundamental cellular process, evidence and rationale indicate that targeting some specific core transcription factors can provide for cancer cell specificity, and that transcription should be pursued as a target for cancer therapy.