The endogenous RNA interference (RNAi) pathway regulates cellular differentiation and development using small noncoding hairpin RNAs, called microRNAs. This chapter will review the link between mammalian microRNAs and genes involved in cellular proliferation, differentiation, and apoptosis. Some microRNAs act as oncogenes or tumor suppressor genes, but the target gene networks they regulate are just beginning to be described. Cancer cells have altered atterns of microRNA expression, which can be used to identify the cell of origin and to subtype cancers. RNAi has also been used to identify novel genes involved in cellular transformation using forward genetic screening methods previously only possible in invertebrates. Possible strategies and obstacles to harnessing RNAi for cancer therapy will also be discussed.