Background: Urothelial carcinoma (UC) is a major cause of mortality with no approved molecularly targeted agents or good treatment options beyond cisplatin-based chemotherapy. Methods: For The Cancer Genome Atlas (TCGA), we profiled muscle-invasive UCs for mutations, DNA copy number variants (CNVs), mRNA and microRNA expression, protein expression and phosphorylation, DNA methylation, transcript splicing, gene fusion, viral integration, pathway perturbation, clinical correlates, and histopathology. The finding here are based on the first 131 tumors, but >250 more are being processed as of 1/2014. Results: Whole-exome sequencing revealed 29 recurrently mutated genes. Potential therapeutic targets included altered PIK3CA, ERBB2, FGFR3, TSC1, and ERBB3, plus mutated chromatin-regulating genes MLL, MLL2, MLL3, CREBBP, CHD7, SRCAP, ARID1A, KDM6A (UTX), and EP300. There were 27 focal CNVs, including CDKN2A deletion in 47%. Low-pass whole-genome sequencing identified 3 tumors with FGFR3-TACC3 fusions. Viral DNA was found in 6% (CMV, HHV6B, HPV16, BK polyoma), and viral transcripts were identified in 4% (CMV, BK polyoma, HPV16). mRNA-seq showed 4 tumor clusters: (I) papillary morphology, FGFR3 dysregulation. (I and II) high HER2 (ERBB2), estrogen receptor beta signaling signature (like Luminal A breast cancer). (III) similar to basal-like breast and squamous cell head and neck. Integrated analyses confirmed changes in cell cycle regulation (93%), kinase and PI3-K signaling (72%), and epigenetic regulation (histone-modifiers: 89%; SWI/SNF nucleosome remodeling complex: 64%). Recurrent defects in PI3-kinase/AKT/mTOR (42%) and RTK/RAS (44%) pathways may be actionable. Conclusions: This study and others identify druggable targets in UC. FGFR3 is activated by mutation, gene fusion, and overexpression, suggesting trials of FGFR3 inhibitors. PI3-kinase/mTOR/AKT/TSC1 pathway defects are frequent, and mutations in TSC1 suggest trial of mTOR inhibitors. ERBB2 amplifications and activating mutations suggest agents such as trastuzumab, trastuzumab-DM1, lapatinib, and neratinib. The mutations in epigenetic regulatory genes suggest potential for chromatin modifying agents.