The renal manifestations of tuberous sclerosis complex (TSC) are remarkably diverse, including polycystic kidney disease, oncocytomas, renal cell carcinomas, and both benign and malignant angiomyolipomas. All of these occur in children as well as adults with TSC. Benign angiomyolipomas, which can cause spontaneous life-threatening hemorrhage, are by far the most prevalent and the greatest source of morbidity. What is particularly unusual about TSC, setting it apart from virtually all other inherited forms of renal disease, is the abnormalities of both mesenchymal cells (angiomyolipomas) and epithelial cells (cysts, oncocytomas, and carcinomas). Recently, the TSC1/TSC2 protein complex was shown to inhibit the kinase mTOR (mammalian target of rapamycin). This places TSC1/TSC2 at center stage in signaling pathways that regulate cell growth. Furthermore, recent advances in TSC1/TSC2 signaling open the door for targeted therapy for TSC patients. Here, we will address the genetic, cellular and biochemical mechanisms that may contribute to the unusually broad spectrum of renal disease in cells with TSC1 or TSC2 mutations, and consider how the TSC signaling pathways may be linked to other renal diseases such as polycystic kidney disease and renal cell carcinoma.