For many years the effect of genetic susceptibility was gleaned through clinical and epidemiologic studies of hereditary syndromes. A major breakthrough in understanding the genetic underpinnings of cancer came in 1971 when Al Knudson described a two-hit mutation model from a statistical analysis of the different age curves as show here for hereditary and non-hereditary forms of retinoblastoma. This study really ushered in the concept of tumor suppressor genes and triggered the race to identify and to clone the first of the inherited genes, RB1.