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Understanding the molecular underpinnings of cancer is of critical importance to developing targeted intervention strategies. Identification of such targets, however, is notoriously difficult and unpredictable. Malignant cell transformation requires the cooperation of a few oncogenic mutations that cause substantial reorganization of many cell features 1 and induce complex changes in gene expression patterns 2-6 . Genes critical to this multi-faceted cellular phenotype thus only have been identified following signaling pathway analysis 7-10 or on an ad hoc basis 4, 11-14 . Our observations that cell transformation by cooperating oncogenic lesions depends on synergistic modulation of downstream signaling circuitry 15-17 suggest that malignant transformation is a highly cooperative process, involving synergy at multiple levels of regulation, including gene expression. Here we show that a large proportion of genes controlled synergistically by loss-of-function p53 and Ras activation are critical to the malignant state. Remarkably, 14 among 24 such 'cooperation response genes' (CRGs) were found to contribute to tumor formation in gene perturbation experiments. In contrast, only one in 14 perturbations of genes responding in a non-synergistic manner had a similar effect. Synergistic control of gene expression by oncogenic mutations thus emerges as an underlying key to malignancy and provides an attractive rationale for identifying intervention targets in gene networks downstream of oncogenic gain and loss-of-function mutations.To identify genes regulated synergistically by cooperating oncogenic mutations at genomic scale, we compared mRNA expression profiles of young adult murine colon (YAMC) cells