The Cancer Genome Atlas (TCGA) sought to identify molecular alterations and classifications, as well as clinically-associated molecular markers of different cancer types, including pheochromocytomas and paragangliomas (PCCs/PGLs). The PCC/PGL TCGA study analyzed 173 primary tumors across several genomic platforms including whole exome sequencing, mRNA sequencing, miRNA sequencing, methylome and reverse phase protein array. This large integrative genomic study offered novel insights into tumorigenesis and aggressive disease. Most PCC/PGL contained a single driver, either as a germline or somatic mutation or fusion gene. This study was the first to identify a recurrent fusion gene in PCC/PGL, which involved MAML3 and lacked the MAML3 canonical NOTCH binding site. In fact, the tumors with the fusion gene did not have upregulation of NOTCH signalling, but instead showed increased Wnt and Hedgehog signalling, suggesting a novel pathway in PCC/PGL tumorigenesis. Furthermore, the presence of the MAML3 fusion gene was associated with clinically aggressive disease. Germline SDHB and somatic ATRX mutations as well as Ki-67 index were reinforced as markers of clinically aggressive disease. In addition, TCGA data confirmed the kinase and pseudohypoxia expression subtypes and identified two novel subtypes, Wnt-altered and cortical admixture. The Wnt-altered subtype tumors were sporadic, associated with clinically aggressive disease, and contained all the tumors with the MAML3 fusion and three of four tumors with somatic CSDE1 mutations, a new somatically mutated gene in association with PCC/PGL. Interestingly, the hypermethylated pseudohypoxia subtype, associated with clinically aggressive disease, contained 74% of the genome-doubled tumors, most of which had VHL or EPAS1 mutations. One limitation to the study is the small number of metastatic tumors in the cohort. Overall, the PCC/PGL TCGA data describe four molecular subtypes with a low genomic alteration rate but diverse driver alterations serving as novel biomarkers for clinically aggressive disease and potential targets for therapy.