Massive genome-wide reprogramming of transcription is critical for malignant transformation. As a consequence, cancer cells are vulnerable to perturbations of the transcriptional apparatus, which includes targeting of DNA-binding transcription factors, transcriptional cofactors, and chromatin regulatory machineries. Over the past 10 years, our lab has taken a genetic screening approach to identify transcriptional dependencies in cancer cells. Upon identifying cancer-specific patterns of gene essentiality, we have pursued detailed molecular mechanisms that underlie these cellular phenotypes. By understanding transcriptional dependencies in cancer, we have revealed fundamental mechanisms of gene control, novel pathways that drive cancer progression, and new therapeutics that reprogram transcription to eliminate cancer cells. The broad goals of our current research are: 1) to discover novel cancer-specific dependencies using next-generation genome editing technology 2) to reveal molecular mechanisms that underlie the addiction of cancer cells to lineage master regulator transcription factors 3) to develop chemical probes that modulate the function of lineage master regulators 4) to explore how cell-of-origin effects and trans-differentiation processes contribute to lung and pancreatic cancer progression.