Over the past 5 years there have been dramatic developments in the extent of knowledge of hereditary renal cancers. In addition to VHL, which is associated with clear cell carcinoma, one can now list HPRC (associated with type I papillary renal cancer) and HLRCC (associated with type II papillary renal cancer). BHD and FRO are associated with chromophobe carcinoma and oncocytomas, although other histologic tumor types have been found in BHD. Medullary carcinoma of the kidney is associated with sickle cell trait. Although the genes associated with these tumors have been discovered, the exact mechanisms by which they cause renal cancer remain to be elucidated. It is quite likely that other genes also are involved in this process. Using VHL as an example, research is now underway on targeting mutant pVHL or excess HIF for diagnostic and therapeutic purposes. Understanding the mechanisms leading to cancer may open new targets of opportunity for drug development. This improved knowledge of the biogenetic pathways used to form tumors will impact the development of new therapeutic techniques for treating renal cancers in hereditary and nonhereditary forms of the disease.