Germline genetics of high penetrance such as BRCA genes, mutations might be sufficient for carcinogenesis, but this only explains fewer than 10% of cancers. We assume that most cancers are the result of germline mutations of low to moderate penetrance, combined with acquired mutations due to external carcinogenic stressors. With their accumulation over time, aging is associated with an increased risk of multiple cancer development in a given individual. For decades, germline genetics have been based on familial linkage studies enabling most high-penetrance genes to be identified. More recently, population-wide studies have led to the identification of considerable numbers of polymorphisms associated with cancer risk. However, most of them are of unknown functional value, thus limiting their translational application.