Genetic heterogeneity explains variation in predisposition for cancer. Whole-genome analysis allows risk to be quantified, giving better targeted screening and quantification of the personalized risk posed by environmental factors. Array-based approaches to whole-genome analysis are rapidly being overtaken by next-generation sequencing (NGS). In this review the different platforms currently available for NGS are compared and the opportunities and risks of this approach are discussed: including the informatics packages required and the ethical issues. Methods applicable to the personal genome machine (PGM) are given as an example of workflows.