Almost all human cancers have accumulated multiple genetic lesions including oncogenes. It is often unknown whether an oncogene is continuously required for tumorigenesis. Furthermore, it is very difficult to target an essential oncogene with drugs without affecting the corresponding nonmutated protooncogene or related factors. The recent discovery of RNA interference and the application of small interfering RNAs in mammalian cell culture provide now tools to examine the role of oncogenes in tumor development. Furthermore, oncogene-specific siRNAs may become promising candidates for more cancer-specific therapeutic approaches. This review discusses the potential and the limitations of oncogene-targeting siRNAs and describes examples for the application of siRNAs in the functional analysis of oncogenes.