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Undermining transcriptional addiction, the dependence of cancers on selected transcriptional programs, is critically important for addressing cancers with high unmet clinical need. Cyclin-dependent kinase 9 (CDK9) has long been considered an actionable therapeutic target for modulating transcription in many diseases. This appeal is due to its role in coordinating the biochemical events that regulate RNA polymerase II (RNA Pol II) pause-release state, one that offers a way for attenuating transcriptional dysregulation driven by amplified or overexpressed transcription factors implicated in cancer. However, targeting CDK9 in the clinic has historically proven elusive, a challenge that stems from the often highly intolerable cytotoxicity attributed to its essentiality across many cell lineages and the polypharmacology of the first generation of pan-CDK inhibitors to reach the clinic. A new wave of highly selective molecules progressing through the early stages of clinical evaluation offers renewed hope.