Current cancer chemotherapies heavily rely on the unspecific inhibition of proliferating cells. This lack of tumour cell specificity results in severe toxic side effects and may only hardly affect quiescent cancer stem cells consequently leading to relapse. Since oncogenes are exclusively expressed in malignant and pre-malignant cells, they may provide unique, cancer cell specific targets for therapeutic strategies. However, their role in maintaining the malignant phenotype is frequently unknown. Furthermore, oncogenic transcription factors are generally considered to be "undruggable" with conventional small molecule approaches. Oncogene-specific RNA interference offers here new and exciting options to analyse oncogene functions directly in the malignant environment. Moreover, such approaches may permit the targeting of oncogenic transcription factors, thereby considerably extending the number of cancer-specific target structures. In this chapter, several rationales and practical aspects of oncogene targeting with siRNAs are discussed. Special emphasis is given to the application of RNA interference to haematopoietic cells, which are generally hard to transfect. In particular, solving the problem of systemic siRNA/shRNA delivery will greatly advance the inclusion of RNA interference strategies into more efficient and specific therapeutic strategies.