The increased molecular understanding of cell growth/death signaling pathways has profoundly affected the development of anticancer drugs towards targeted therapies.Genes for whom activity, expression or dependence is thought to have increased in cancer are prime candidates for therapeutic intervention; cancer cells may depend upon such changes in gene expression not only during tumor initiation, but also during malignancy progression (i.e."oncogene addiction").This is exemplified by the choice of oncogenes as drug targets such as: the BCR-ABL fused protein in CML,ERBB2/HER2 amplification in a subtype of breast carcinomas, ERBB 1/EGFR in non-small cell lung cancer (NSCLC),the VEGF receptor in colon and pancreatic cancers, etc.Alternatively, using the concept of synthetic (synergistic)lethality, efforts have been directed toward identification of either chemicals/drugs or target genes whose activation or ablation, respectively, synergizes with mutations in either oncogenes or tumor suppressor genes (rev.in Canaani 2009).In this talk I will review the major achievements in application of the chemical and genetic synthetic lethality screens towards cancer in general, and breast cancer in particular.Special emphasize will be devoted to describing the pooled RNAi (shRNA encoded viral libraries) negative selection screening, its advantages and limitations.