Broad alterations in the rate of gene transcription are required for cells to undergo malignant transformation. As a consequence, cancer cells are vulnerable to perturbations of transcriptional regulators, including DNA-binding transcription factors and chromatin proteins. Our laboratory has taken a functional-genomics approach to identify essential transcriptional regulators in cancer with “oncogene-like” properties, thereby exposing opportunities for therapeutic intervention. Our initial efforts used RNAi screening to identify the BET bromodomain protein BRD4 as a targetable oncogene-like dependency in acute myeloid leukemia. Over the past few years, we have advanced our mechanistic understanding of BRD4 as a therapeutic target in leukemia by revealing the upstream and downstream factors that support BRD4-dependent transcriptional activation. More recently, we have pursued the use of domain-focused CRISPR-Cas9 screening as a tool for annotating essential transcriptional regulators and signaling molecules in cancer, which exploits the heterogeneity of Cas9-induced indel mutations to infer structure-function relationships of individual protein domains.