Genomic alterations in diverse cell types at different sites in the body give rise to hundreds of different forms of cancer, and the ways in which these changes result in tumors with different biology, pathology and treatment strategies are beginning to be characterized. The TCGA Research Network has catalogued aberrations in the DNA, chromatin and RNA of the genomes of thousands of tumors relative to matched normal cellular genomes and has analyzed their epigenetic and protein consequences. Here the Pan-Cancer initiative examines the similarities and differences among the genomic and cellular alterations found in the first dozen tumor types to be profiled by TCGA. This first look across cancer types offers new tools in genomics and bioinformatics and the prospect of repurposing targeted therapies directed by the molecular pathology of the tumors in addition to their clinical classification.