Abstract Introduction: Small Cell Lung Cancer (SCLC) is a highly aggressive lung tumor with a 5 year survival rate of only 5% for extensive stage disease, which has only modestly improved over the last few decades. Identification of new molecular diagnostic and therapeutic targets is thus imperative. The purpose of this study was to employ genomic profiling of SCLC tumors to identify novel genomic alterations responsible for driving the aggressive biology of SCLC. Methods: DNA was extracted from a panel of 14 formalin fixed paraffin embedded SCLC tumors and used to perform high resolution array comparative genomic hybridization (aCGH) on a tiling array to identify recurrent copy number alterations. RNA was harvested from a series of SCLC cell lines and used to perform qRT-PCR on candidate genes. Publicly available SCLC tumor microarray data was also analyzed to interrogate the expression of candidate genes. Results: Through application of integrated genome and transcriptome microarray profiling, and comparison of SCLC to less aggressive non-small cell lung cancers (NSCLC) we have identified novel patterns of genomic alteration mediated pathway disruption specific to SCLC. This includes activation of the cell cycle through deregulation of downstream pathway components, as opposed to upstream deregulation of receptors such as EGFR which is characteristic of NSCLC. Strikingly we observed direct genomic activation of E2F transcription factors, in addition to the classically described loss of the Rb tumor suppressor. Analysis of targets of the E2F/Rb pathway identified EZH2, a polycomb repressive complex 2 (PRC2) member involved in epigenetic silencing of genes involved in differentiation. EZH2 has been characterized as a target of genomic amplification in prostate and breast cancers, however, no genomic amplifications were detected in our SCLC samples, thus any overexpression is likely regulated by upstream elements of the E2F/Rb pathway. qRT-PCR confirmed EZH2 as being specifically hyper-activated with a mean 42 fold over-expression (range 10 to 74 fold) in SCLC compared to 13 fold in NSCLC. This pattern was verified from an analysis of an independent array study of SCLC. Moreover, shRNA-mediated knockdown demonstrated a significant reduction in cell viability in SCLC cell lines. Conclusion: We conclude that EZH2 activation through genomic alteration of E2F/Rb contributes to the malignant phenotype of SCLC and may represent a potential therapeutic target.