In spite of early observations indicating an association of cancer with genomic alterations, the precise knowledge of the causal mutations was only initiated since the last 20 years when the techniques of molecular genetics were applied to observations obtained by investigators working in the field of retrovirology, cell biology, cytogenetics and human genetics. A large number of genes which are recurrently altered in defined tumor types has been identified. Schematically it is possible to distinguish dominant mutations which lead to the oncogenic conversion of proto-oncogenes and recessive mutations of antioncogenes which require for phenotypic expression the inactivation of the second allele. Activation of protooncogenes and inactivation of antioncogenes cooperate within the same cells to the determination of the tumor phenotype. Inherited alterations causing major predisposition to tumor development involve most frequently antioncogenes. Most proto-oncogenes and major tumor susceptibility genes are now known. However, we have a poor understanding of the pathologic mechanism triggered by their mutations.