The next phase of genetic discovery will be to identify genes that contribute to the heritable component of the cause of cancer, but are not sufficiently influential to account for families with a classic pattern of inheritance of cancer. The gene CHEK2 occupies a critical role in cell cycle control. Association studies within cases of familial breast cancer have identified mutations in this gene as being a significant risk factor in predisposition to breast cancer. In most cases, defective function of at least one other unidentified gene is needed to precipitate disease. Such genes, which confer a mild to moderate increase in predisposition, are likely to interact with environmental triggers to lead to cancer in a proportion of people with the at risk genotype. These developments will lead to a growing list of genetic variations in the population being identified as conveying an increased risk of malignancy. The major challenge will be to quantify the risk associated with such genetic variation in different environmental settings. It is likely that a range of biases will lead to several such associations being assigned an inappropriate significance. Large scale population based evaluation will be needed, such as will become possible with the new Biobank UK project, before these moderate risk genes can be incorporated into clinical practice.