Background: The most frequent genomic alterations in patients (pts) with ccRCC have been identified in primary tumors. Here we investigated the genomic landscape of ccRCC in a cohort enriched for metastatic tumors after treatment with systemic therapy. Methods: We prospectively enrolled pts with ccRCC in a clinical study in which Whole-Exome Sequencing (WES) of normal and tumor tissue was performed. Clinical features, treatment outcome and survival were evaluated. Results: Forty-five pts with ccRCC with a median age of 65 years (range 38–86) were enrolled. According to the Heng risk criteria, 15 pts (33.3%) were classified as favorable-risk 23 pts (51.1%) were intermediate-risk and 7 pts (15.6%) were poor-risk. Pts received a median number of 3 lines (range 0–9) of therapy including cytokines (n=7), anti-VEGF (n=36), mTOR inhibitors (n=10) and/or immune checkpoint inhibitors (n=23). The median progression free survival (PFS) after treatment was 3.5 months (0.7-13.1), 11.1 months (1.1–54.2), 2.7 months (0.7-36.2) and 4.9 months (1.4–29.2) after cytokines, VEGF-, mTOR- and immune checkpoint inhibitors, respectively. The median overall survival (OS) from start of treatment to last follow up was 2.2 years (range 0.2–14.9 years). A total of 68 samples were sequenced. These included 9 (12.5%) primary tumors, 38 (55.9%) collected after treatment with anti-VEGF, 16 (23.5%) after mTOR- and 8 (11.8%) after immune checkpoint inhibitor. VHL, KDM5C, SETD2 and PBRM1 were the most frequent somatic mutations detected in this cohort. In two cases with a short and long response to VEGF targeted therapy (PFS 2.8 versus 50.3 months) rapid autopsies were performed which allowed multiregional (n=7, n=4) sampling. The multiregional sequencing in the rapid autopsy case with a prolonged response to VEGF targeted therapy revealed recurrent KDM5C mutations. Conclusions: We present the genomic landscape of metastatic ccRCC after treatment with systemic therapy. We report an increased frequency of KDM5C mutations, previously described to be associated with a favorable response to VEGF-inhibitors.