Renal Cell Carcinoma (RCC) is the most common type of kidney cancer, with over 270,000 new cases diagnosed annually worldwide, leading to more than 116,000 deaths each year. RCC typically progresses asymptomatically, with symptoms often appearing only at advanced stages, resulting in a poor prognosis. Surgical intervention may lead to relapse or metastasis in 20-30% of patients within five years, particularly in advanced RCC cases where treatment options remain limited. This complexity is compounded by the heterogeneity of RCC, characterized by distinct genetic mutations influencing its progression. Clear Cell RCC (ccRCC), the most common RCC subtype, is primarily driven by mutations in the VHL gene and chromatin-regulating genes such as BAP1, PBRM1, and SETD2. These mutations have been linked to the onset of metastasis and poor disease-free survival. Notably, mutations in PBRM1 and SETD2 play pivotal roles in the genetic evolution of ccRCC, influencing tumor genesis and metastatic potential. A comprehensive understanding of these genetic alterations is crucial for advancing clinical practices in oncology. This review highlights the importance of the PBRM1 and SETD2 genes in ccRCC, proposing that their mutations may not only serve as tumor initiators but also contribute to the metastatic spread of the disease. The insights presented here emphasize the need for continued research into these genetic drivers, which could potentially lead to the development of novel therapeutic strategies for RCC. The integration of these findings into broader research initiatives offers the potential for transformative advancements in RCC treatment, ultimately improving patient outcomes.