The development of renal cell neoplasms ranging from adenoma to metastatic carcinoma is the most serious complication of acquired cystic kidney disease (ACKD). A comprehensive review of the pertinent literature shows that there is up to 50-fold increased risk of renal cell carcinoma in ACKD compared to the general population. The ACKD-associated renal cell carcinoma is seen predominantly in males, occurs approximately 20 years earlier than in the general population, and is frequently bilateral (9%) and multicentric (50%). Acquired cystic kidney disease-associated renal cell carcinoma is frequently asymptomatic (86%), but may be associated with bleeding, abrupt changes in hematocrit, fever, and flank pain or rarely with hypoglycemia, hypercalcemia, or metastases at presentation. Computed tomography seems to provide a better diagnostic yield than sonography or magnetic resonance imaging; nevertheless, large (up to 8 cm) tumors not visualized by any imaging techniques have been reported. It is generally agreed that there is a need for regular screening of symptomatic ACKD patients for early detection of renal cell carcinoma; however, whether screening is needed for asymptomatic patients remains controversial. Nephrectomy is indicated for tumors larger than 3 cm. Management for tumors smaller than 3 cm with persistent symptoms, such as back pain or hematuria, remains controversial, but nephrectomy may be recommended since many of these tumors turn out to be unequivocal renal cell carcinoma. Asymptomatic tumors smaller than 3 cm should be serially screened, and tumor enlargement may be an indication for nephrectomy. Acquired cystic kidney disease-associated renal cell carcinoma accounts for approximately 2% of deaths in renal transplant patients. A median length of survival of approximately 14 months and a 5-year survival rate of 35% are comparable to the same data for renal cell carcinoma in the general population. Successful renal transplant probably decreases the risk of renal cell carcinoma in ACKD patients, but this preliminary observation needs confirmation. The development of ACKD-associated renal carcinoma is a continuous process with evolving phenotypic expression, including damaged renal tubule, simple cyst, cyst with atypical lining, adenoma, and, finally, carcinoma. The pathogenesis of this continuous process is not entirely known, but growth factor-induced compensatory growth of tubular epithelium initiated by the changes of end-stage kidney disease, and probably perpetuated by activation of proto-oncogenes, seems to be the most significant factor.