Cancer is driven by mutation. Using massively parallel sequencing technology, we can now sequence the entire genome of cancer samples, allowing the generation of comprehensive catalogues of somatic mutations of all classes. Bespoke algorithms have been developed to identify somatically acquired point mutations, copy number changes and genomic rearrangements, which require extensive validation by confirmatory testing. The findings from our first handful of genomes illustrate the potential for next-generation sequencing to provide unprecedented insights into mutational processes, cellular repair pathways and gene networks associated with cancer development. I will also review possible applications of these technologies in a diagnostic and clinical setting, and the potential routes for translation.