Renal cell carcinoma (RCC), although occurring less frequently than prostate and bladder cancer, is actually the most malignant urologic disease, killing >35% of affected patients. Therefore, investigation of the nature of premalignant lesions of the kidney is a relevant issue. Following the most recent histological classification RCC can be subdivided into four categories: conventional RCC; papillary RCC; chromophobe RCC; and collecting duct carcinoma. In contrast to many genitourinary malignancies, premalignant alterations in the kidney are scarcely described. Intratubular epithelial dysplasia has been recognized as the most common precursor of RCC. In analogy to prostatic intraepithelial neoplasia (PIN), the premalignant lesions of the kidney are described as high or low-grade renal intratubular neoplasia. In contrast, precancerous lesions have been described as part of the von Hippel-Lindau syndrome (VHL) where the evolution from a simple cyst to an atypical cyst with epithelial hyperplasia to cystic or solid conventional-type RCC is well documented. Finally, in the genesis of papillary RCC an adenoma-carcinoma sequence has been recognized with specific genetic changes. There are no data on the epidemiology of premalignant lesions of the kidney, but research into the etiology of RCC has been extended substantially. Familial and genetic factors are well documented in VHL disease, in hereditary papillary RCC, in the tuberous sclerosis complex and in familial RCC. Cigarette smoking and obesity are established risk factors for RCC. Hypertension or its medication has also been associated with an increased risk. Among dietary factors an inverse relation between risk and consumption of vegetables and fruit has been found. Occupational exposure to substances such as asbestos and solvents has been linked to an increased risk of RCC. Specific RCC variants have distinctive chromosome alterations and several genes have been implicated in the development of RCC. Loss of material from the 3p chromosome characterizes conventional RCC and the deletion of the VHL suppressor gene plays an important role in the genesis of this RCC variant. In contrast, numerical changes with trisomy of chromosomes 7 and 17 and loss of the sex chromosome are typical changes in papillary tumors, whereas papillary RCC have additional trisomies. Chromophobe RCC is characterized by loss of chromosomes with a combination of monosomies. Less consistent genetic alterations are associated with collecting duct carcinoma. The traditional treatment of RCC is surgery by radical or partial nephrectomy. The latter approach carries a risk of tumor recurrence as a result of unrecognized satellite lesions or premalignant lesions that might have been present at the time of surgery. However, the reported recurrence rates after partial nephrectomy are <1% and therefore the possible presence of premalignant disease does not alter the actual treatment strategy advocated. Although multifocality and bilateral occurrence of RCC are much more likely in cases of papillary RCC, biopsy of the renal remnant or contralateral kidney is not justified even in patients with this tumor type. Conversely, patients with RIN in a partial or radical nephrectomy specimen or in a renal biopsy taken for whatever reason should be subjected to closer follow-up with regularly repeated ultrasound. When an effective chemopreventive regimen becomes available it might be useful for patients with an inherited risk of RCC as well as in those who are at risk of tumor recurrence after intervention. Mass screening with the purpose of detecting RCC at its earliest stage is not recommended at the present time, but screening focused on certain risk groups can be advocated. Further research is needed to identify avoidable risks, develop effective chemoprevention and recognize patients at risk.