Familial adenomatous polyposis (FAP) has become the focus of several convergent lines of scientific and medical enquiry. The year 2000 has seen the completion of the human genome project and this coincides with the next major challenge of cancer genetics, non-mendelian inheritance. Colorectal cancer remains a major source of morbidity and mortality in developed countries. Despite huge advances in understanding the pathology of the disease, its mortality has remained virtually unchanged in 50 years. The disease is curable if detected early, yet screening strategies for the general population have been largely unsuccessful. FAP is a superb model for sporadic colorectal cancer. If the genetic and other causes of variation in the FAP phenotype can be understood, this knowledge will have a dividend for the general population and may lead to new approaches for screening for colorectal cancer. This article discusses current knowledge of how the clinical features of FAP patients vary, with emphasis on the role of modifier genes, and discusses strategies for their identification.