BACKGROUND In the current study, the authors present a comprehensive genomic profile (CGP)‐based study of advanced urothelial carcinoma (UC) designed to detect clinically relevant genomic alterations (CRGAs). METHODS DNA was extracted from 40 µm of formalin‐fixed, paraffin‐embedded sections from 295 consecutive cases of recurrent/metastatic UC. CGP was performed on hybridization‐captured, adaptor ligation‐based libraries to a mean coverage depth of 688X for all coding exons of 236 cancer‐related genes plus 47 introns from 19 genes frequently rearranged in cancer, using process‐matched normal control samples as a reference. CRGAs were defined as GAs linked to drugs on the market or currently under evaluation in mechanism‐driven clinical trials. RESULTS All 295 patients assessed were classified with high‐grade (International Society of Urological Pathology classification) and advanced stage (stage III/IV American Joint Committee on Cancer) disease, and 294 of 295 patients (99.7%) had at least 1 GA on CGP with a mean of 6.4 GAs per UC (61% substitutions/insertions/deletions, 37% copy number alterations, and 2% fusions). Furthermore, 275 patients (93%) had at least 1 CRGA involving 75 individual genes with a mean of 2.6 CRGAs per UC. The most common CRGAs involved cyclin‐dependent kinase inhibitor 2A (CDKN2A) (34%), fibroblast growth factor receptor 3 (FGFR3) (21%), phosphatidylinositol 3‐kinase catalytic subunit alpha (PIK3CA) (20%), and ERBB2 (17%). FGFR3 GAs were diverse types and included 10% fusions. ERBB2 GAs were equally divided between amplifications and substitutions. ERBB2 substitutions were predominantly within the extracellular domain and were highly enriched in patients with micropapillary UC (38% of 32 cases vs 5% of 263 nonmicropapillary UC cases; P<.0001). CONCLUSIONS Using a CGP assay capable of detecting all classes of GA simultaneously, an extraordinarily high frequency of CRGA was identified in a large series of patients with advanced UC. Cancer 2016;122:702–711. © 2015 American Cancer Society. Advanced urothelial carcinoma is an invariably fatal disease, and there is a lack of effective, approved systemic therapies beyond first‐line platinum‐based chemotherapy. In the current study, the authors identify a high frequency of clinically relevant genomic alterations in a large cohort of patients with advanced disease. Conceivably, these results could inform the rational design of clinical trials of targeted therapies for patients with advanced urothelial carcinoma.