RNA interference is the process by which double-stranded RNA directs sequence-specific degradation of mRNA. It has recently been shown that RNA interference can be triggered by 21-nucleotide duplexes of small interfering RNAs (siRNAs) in both cultured mammalian cells and adult mice. We hypothesize that siRNA can be used to specifically target oncogene overexpression in a therapeutic manner. Here, we show that overexpression of the oncogene cyclin E can be suppressed by up to 90% in hepatocellular carcinoma (HCC) cell lines by siRNA targeted on the coding region of cyclin E. We also find that depletion of cyclin E in this manner promotes apoptosis of HCC cells and blocks cell proliferation. Finally, we show that the siRNA oligos inhibits HCC tumor growth in nude mice. Thus, this study demonstrates the therapeutic potential of siRNA on the treatment of HCC by targeting overexpressed oncogenes such as cyclin E. Our results also indicate that cyclin E, which is overexpressed in 70% of HCCs, may serve as a novel therapeutic target.