Recent technological advances now permit the study of the entire cancer genome, which can elucidate complex pathway interactions that are not apparent at the level of single genes. In this review, the authors describe innovations that have allowed for whole-exome/genome analysis of genetic and epigenetic alterations and of changes in gene expression. Studies using next-generation sequencing, array comparative genomic hybridization, methylation arrays, and gene expression profiling are reviewed, with a particular focus on findings from recent whole-exome sequencing projects. A discussion of the implications of these data on treatment and future goals for cancer genomics is included.