Abstract In rapidly progressing cancers, appropriate selection of first-line therapy is essential in prolonging survival. Alongside immunohistochemistry (IHC), comprehensive genomics, including whole exome and transcriptome sequencing (WES/WTS), can improve diagnostic accuracy and guide therapeutic management. Here, we report a young patient with rapidly progressing malignancy and unexpected post-mortem results, a scenario that may have been altered by early, comprehensive genomic sequencing. A 43-year-old man with no relevant medical history presented to the emergency department with progressive cough and dyspnea despite treatment for pneumonia. Radiology revealed enlarged subcarinal, hilar, retroperitoneal, and mesenteric lymph nodes, suspicious for metastasis, and a right kidney mass. Pathologic analysis of a retroperitoneal lymph node was felt to be most consistent with metastatic epithelioid angiomyolipoma (mEAML). Three weeks later, he was urgently treated with an mTOR inhibitor for presumed mEAML due to rapid clinical decline, and a subsequent 4R lymph node biopsy was performed to confirm the diagnosis and identify genomic targets via IHC and WES/WTS. Unfortunately, he developed hypoxic respiratory failure, and only posthumously did WES/WTS reveal pathogenic variants in BAP1 and VHL, consistent with clear cell renal cell carcinoma (ccRCC). With an earlier ccRCC diagnosis, he would have received combination immunotherapy/tyrosine kinase inhibition, which has significantly greater activity than mTOR inhibition in ccRCC. He could have received systemic treatment earlier, with optimal therapy, while potentially carrying lower tumor burden and greater clinical stability. In cases of rapidly progressing malignancies with complex histopathological presentations, early comprehensive molecular-based testing can aid in diagnosis and critical therapeutic decision-making.