Massive reprogramming of transcription is critical for malignant transformation. Consequently, cancer cells are vulnerable to perturbations of the transcriptional machinery, which includes targeting of DNA-binding transcription factors, transcriptional cofactors, and chromatin regulators. Over the past 10+ years, our lab has taken a genetic screening approach to identify unique and novel transcriptional dependencies of cancer cells, followed by pursuit of detailed molecular mechanisms that account for these cancer-specific requirements. These efforts have revealed fundamental mechanisms of gene regulation, novel pathways that drive cancer evolution, and new therapeutics that reprogram transcription to eliminate cancer cells.