Cancers are driven by genomic and epigenetic alterations that result in the activation of cellular proto-oncogenes and the inactivation of tumor suppressor genes. Although high-throughput genomic approaches have begun to establish extensive catalogs of gene alterations in human tumors, the genes that control tumor genesis, progression and response to therapies are often concealed by the complex chromosomal instability in cancer cell genomes. This challenge is exacerbated by the lack of functional annotation for the vast majority of genes in the human genome. Thus, functional approaches are critical for identifying the genetic programs underlying cancer pathogenesis. Our laboratory applies genome-wide RNA interference (RNAi) and other technologies to the unbiased discovery of cancer genes and networks. Specifically, we focus on four areas of cancer gene discovery: Discovering new oncogene-induced “stress pathways” and translating these pathways into cancer therapies