There is an ever growing report of data supporting the evidence that accumulated genetic changes underlie the development of neoplasia. The paradigma of this multistep process is colon cancer were cancer onset is associated, over decades, with at least seven genetic events. The number of genetic alterations increases moving from adenomatous lesions to colon cancer and, although the genetic alterations occur according to a preferred sequence, the total accumulation of changes rather than their sequential order is responsible of tumor biological behavior. It is noteworthy that, at least for this neoplasia, carcinogenesis appears to arise as a result of the mutational activation of oncogenes coupled with the mutational inactivation of tumor suppressor genes. In some cases mutant suppressor genes appear to exert a phenotypic effect even when present in the heterozygous state thus been non "recessive" at the cellular level. The general features of this model may apply also to renal cell cancer (RCC) and prostate cancer (CaP). Extensive literature exists on the cytogenetic and molecular findings in RCC. Only 2% of RCC are familiar, but molecular genetic studies of these cancers have provided important informations on RCC pathogenesis. As with other cancers, familiar RCC is characterized by an early age of onset and frequent multicentricity. A pathological classification useful in studying these patients subdivide renal cancers in papillary (pRCC) and non papillary (RCC) neoplasms. The most common cause of inherited RCC is the Von Hippel Lindau disease (VHL) a dominantly inherited multisystem disorder characterized by retinal and cerebellar hemangioblastomas, pheochromocytomas, pancreatic cysts and RCC. Over 70% of these patients will develop an RCC by their sixth decade. In 1993 the isolation of the tumor suppressor gene in VHL disease at the level of chromosome 3p25-p26 have lead to a better understanding of RCC. Most missense mutations are associated with high risk of RCC, but some are associated with high risk of pheochromocytoma and low risk of RCC. The VHL gene is evolutionary conserved and encodes for a specific protein (pVHL). VHL protein downregulates transcriptional elongation and so suppresses the expression of proto-oncogenes and growth factors. Recently reintroduction of wild-type, non mutant, VHL gene into VHL deficient RCC cell line 786-O had no demonstrable effect on their in vitro growth but inhibited their ability to form tumors in nude mice. So far, VHL mutations or hypermethylations have been found in 76% of sporadic RCC. On the contrary, up to now, no 3p allele loss or VHL mutations have been detected in pRCC. Preliminary studies in familiar pRCC are pointing on genetic changes on chromosomes 1, 7, 16 and 17. As far as prostate cancer is regarded, men with a family history of prostate cancer have an age dependent, significantly increased PCa risk. For familiar clustering, of PCa the two main factors are early age at onset of the disease and the number of multiple affected family members. Hereditary prostate cancer is a subset of familiar prostate cancer with a pattern of distribution consistent with Mendelian inheritance. Hereditary prostate cancer is clinically defined as a clustering of 3 or more relatives within any nuclear family; or the occurrence of prostate cancer in each of 3 generations in either the probands paternal or maternal lineage; or a cluster of 2 relatives affected within 55 years of age or less. Therefore, hereditary prostate cancer may be seen as a multistep carcinogenesis, and clustering may be explained by Mendelian inheritance of a rare (frequency in population 0.36%) dominant, highly penetrant, allele. The estimated cumulative risk of developing PCa, is 88% for carriers as compared with 5% for non carriers. There are conflicting reports of an associated increased incidence of breast cancer in female relatives of men with familiar prostate cancer. In conclusion, there is a clear associatio