Advances in DNA sequencing technology are about to transform healthcare. Since completion of the human genome reference sequence ten years ago, there has been a 1-million fold improvement in the rate of sequence data generation (bases/day/instrument). As a result, it is now possible to decode a person’s genome and return the annotated sequence for biological and clinical interpretation in a few days. Current research is focussed on refining methods for sequencing real-world clinical samples, benchmarking accuracy, refining variant calling, improving annotation and reporting, and in developing process workflows to enable whole genome sequencing at a national scale. Early applications of clinical whole genome sequencing include detection of mutations in patients suffering rare genetic disease or cancer. Aggregation of individual genome sequences alongside clinical and other phenotypic information will create an integrated knowledgebase that underpins a new era of genomic medicine.