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Clear cell ovarian and kidney cancers are rare but aggressive cancers characterized by resistance to traditional chemotherapies. The transcriptional drivers of these tumors are poorly understood, but the histologic similarities suggest that a subset of common factors may drive differentiation of the clear cell phenotype, agnostic of anatomic origin. Master transcription factors (MTFs) are the essential transcriptional regulators that create interconnected auto-regulatory circuits critical for tumor cell survival. Candidate MTFs can be identified due to their characteristic high level, tissue-specific expression, functional essentiality in tumor models, and participation in interconnected core regulatory transcriptional circuits. We collated 5 high grade serous ovarian cancer, 5 clear cell ovarian cancer, 5 papillary renal cell cancer and 11 clear cell renal cell cancer primary tissue and 27 cell line data sets for clear cell ovarian and kidney cancers, and non-clear cell tumors of the same organs. We integrated gene expression, super-enhancer landscapes and global maps of open chromatin to identify candidate MTFs specific to clear cell tumors. This identified known Hepatocyte nuclear factor-1-beta (HNF1B), commonly over-expressed in >90% of clear cell cancers and other novel candidates, including RARA, which encodes retinoic acid receptor alpha. Clear cell kidney and ovarian cancer cell lines are often co-dependent on sustained expression of HNF1B and RARA for survival, suggesting perturbed retinoic acid signaling represents a novel therapeutic target for clear cell tumors. Transcriptional inhibitors provide a novel therapeutic target for many cancers that may otherwise be chemoresistant. Clear cell lines are particularly sensitive to general transcriptional inhibitors in in-vitro models; functional analyses are ongoing to determine the role of RARA, HNF1B and other factors in explaining these responses. Citation Format: Marla Elizabeth Scott, Robbin Nameki, Forough Abbasi, Marcos Abraao de Souza Fonseca, Rosario (Ivetth) Corona de la Fuente, Kate Lawrenson. Core regulatory circuits of clear cell ovarian and kidney cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2433.