Study design in understanding gene—environment interaction plays a crucial role. Different study designs with their advantages and limitations are described in this chapter. Gene penetrance has been studied in several cancers, including breast and prostate cancer. Compared with high-penetrance genes, such as breast cancer (BRCA)1, BRCA2 in breast cancer, gene—environment interaction plays a major role in cancer development where low-penetrance genes are the major players. Genetic polymorphism is determined in low- and high-penetrance genes to identify cancer-related polymorphisms. The role of genetic and epigenetic factors in cancer development is discussed. Preventive approaches, especially in the epigenetic field, show promise. A discussion about different epidemiological methods with examples is provided.