AbstractThe term ‘single‐molecule genomics’ (SMG) describes a group of molecular methods in which single molecules are detected or sequenced. The focus on the analysis of individual molecules distinguishes these techniques from more traditional methods, in which template DNA is cloned or PCR‐amplified prior to analysis. Although technically challenging, the analysis of single molecules has the potential to play a major role in the delivery of truly personalized medicine. The two main subgroups of SMG methods are single‐molecule digital PCR and single‐molecule sequencing. Single‐molecule PCR has a number of advantages over competing technologies, including improved detection of rare genetic variants and more precise analysis of copy‐number variation, and is more easily adapted to the often small amount of material that is available in clinical samples. Single‐molecule sequencing refers to a number of different methods that are mainly still in development but have the potential to make a huge impact on personalized medicine in the future. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.