Background: At ESMO 2025, practice-changing advances in genitourinary oncology emerged for renal cell carcinoma (RCC) and muscle-invasive bladder cancer (MIBC), highlighting a shift toward early systemic treatment and biomarker-driven treatment selection. Summary: In localized RCC, the NESCIO trial showed pathologic responses with short-course neoadjuvant checkpoint inhibition, while the RAMPART study supported adjuvant dual checkpoint blockade for high-risk disease. For advanced RCC, the KEYMAKER-U03 trial demonstrated improved progression-free survival with a novel HIF-2α triplet regimen, and the LenCabo study supported the use of lenvatinib plus everolimus in later treatment lines. Conversely, the CALYPSO trial noted limited benefit when using empiric combinations without precise biomarker selection. In cisplatin-ineligible MIBC, the KEYNOTE-905/EV-303 trial demonstrated a significant survival benefit with perioperative enfortumab vedotin plus pembrolizumab. Finally, emerging data from OPTIC RCC transcriptomic stratification and circulating markers like kidney-injury molecule type 1 and circulating tumor DNA strongly support a broader transition toward tailored therapy. Key Messages: Perioperative enfortumab vedotin plus pembrolizumab offers a major survival benefit for cisplatin-ineligible bladder cancer patients. Overall, early-stage RCC benefits significantly from perioperative immunotherapy, while managing advanced disease requires a decisive shift away from empiric combinations and toward biomarker-driven treatment selection.