Whole-genome sequencing (WGS) of pathogens is becoming increasingly important not only for basic research but also for clinical science and practice. In virology, WGS is important for the development of novel treatments and vaccines, and for increasing the power of molecular epidemiology and evolutionary genomics. In this Opinion article, we suggest that WGS of viruses in a clinical setting will become increasingly important for patient care. We give an overview of different WGS methods that are used in virology and summarize their advantages and disadvantages. Although there are only partially addressed technical, financial and ethical issues in regard to the clinical application of viral WGS, this technique provides important insights into virus transmission, evolution and pathogenesis. ; Other ; CJH was funded by Action Medical Research grant GN2424. MAB was funded through the European Union’s Seventh Programme for research, technological development and demonstration under grant agreement No 304875 held by JB. This work was supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. JB receives funding from the UCLH/UCL National Institute for Health Research Biomedical Research Centre. The authors acknowledge infrastructure support for the UCL Pathogen Genomics Unit from the UCL MRC Centre for Molecular Medical Virology and the UCLH/UCL National Institute for Health Research Biomedical Research Centre.