Renal cell carcinoma (RCC) represents the sixth-leading cancer-specific cause of death worldwide. This is mainly caused by metastatic or locally advanced RCC. Approximately 25-30% of patients present with metastasis during the initial diagnosis. Furthermore, 20-30% of patients develop metastatic disease following initial curative surgery. Metastatic RCC is characterized by a poor prognosis with a median overall survival of less than 2 years. Today, targeted therapies such as VEGF receptor inhibitors and antagonists as well as mTOR inhibitors represent the standard of care in metastatic RCC. Conventional chemotherapies or cytokine-based medications have been abandoned due to inferior clinical efficacy compared with targeted therapies. In Germany, sunitinib, pazopanib, temsirolimus, and bevacizumab have been approved for first-line treatment and sorafenib, axitinib, and everolimus for second-line treatment. Prognostic models, assessing individual risk profiles, have been developed in the last 15 years, which are crucial for the design of trials, patient counseling, and initiation of goal-directed therapies.