Renal cell carcinoma (RCC) is a diverse group of cancers originating from renal tubular epithelial cells and ranks among the top 10 most common cancers worldwide1. An estimated 403,000 people a year are diagnosed with neoplasms of the kidney, constituting 2.2% of all cancer diagnoses2. Of these, approximately 254,500 cases are diagnosed in males and 148,800 in females, reflecting a relative risk (RR) of about 1.7 for men compared to women2. Advances in histopathological and molecular characterization of RCC in the past two decades have led to significant revisions in its classification3, 4, 5, 6. The major subtypes7, with an incidence of ≥5%, include clear cell RCC (ccRCC)8, papillary RCC (pRCC)9, and chromophobe RCC (ChRCC)10,11. Sporadic renal cell carcinoma represents the vast majority (about 90-95%) of RCC. Sporadic RCC is a disease of older adults, with the average of diagnosis in the US is 6412. When RCC is diagnosed at younger ages (≤46 years)12,13, consideration should be given to the possibility of an underlying hereditary kidney cancer syndrome, which accounts for 3-5% of all RCC cases14, 15, 16. Multiple predisposition syndromes have been identified, including Von Hippel-Lindau syndrome, BAP1-Tumor Predisposition Syndrome, Hereditary Papillary Renal Cell Carcinoma, Tuberous Sclerosis Complex, Birt-Hogg-Dubé syndrome, Hereditary Paraganglioma–Pheochromocytoma Syndrome, Fumarate Hydratase Tumor Predisposition Syndrome, and Cowden syndrome. Prior reviews have focused on the clinical and pathologic manifestations14,16, 17, 18, 19 of these syndromes and in many cases the key signaling pathways that lead to tumor formation and progression20,21. Here, we will focus on the shared genetic pathways between syndromic and sporadic cases, delineating the common threads that link hereditary predispositions to the development of sporadic RCC (Figure 1), and highlighting key unknowns and opportunities for improved diagnostic strategies, risk assessment, and targeted therapies. Unraveling the genetic complexities linking familial syndromes to sporadic RCC may reveal novel therapeutic targets and advance the opportunities for precision medicine.