Cancers are caused by the accumulation of genomic and epigenomic alterations. Particularly, genetic alterations, such as BCR-ABL translocation and EGFR mutation, which are present only in cancer cells, are the best therapeutic targets to date. The application of next-generation DNA sequencing technologies, including whole-genome, whole-exome and whole-transcriptome approaches, has brought substantial advances in cancer genomics. These methods will increase the efficiency and resolution of detection of somatic cancer genome alterations, including nucleotide substitutions, small insertions and deletions, copy number alterations, and chromosomal rearrangements. Currently, an international network of cancer genome projects was launched to coordinate large-scale cancer genome studies. The greatest impact of next-generation sequencing of cancer genomes in the near future will be in cancer diagnostics. To provide personalized cancer treatment, development of accurate genetic diagnostic tests and biomarkers is required and will surely be accelerated by next-generation sequencing technology.