Renal cell carcinona is the most common kidney tumor. In Israel more than 600 cases are diagnosed annually. Risk factors for renal cell carcinoma include obesity, smoking, hypertension, and diabetes; 20-30% of the patients are diagnosed with metastatic disease, and 70-80% of patients are diagnosed with an early non-metastatic tumor. The treatment of an early non-metastatic tumor is resection. At present, the role of adjuvant systemic therapy has not been established; 20-40% of the patients operated on for an early tumor will suffer from metastatic disease recurrence. The lungs are the most common site of metastases. Renal cell carcinoma is relatively refractory to chemotherapy and radiation. In the last decade, an improved understanding of the biology of the tumor, led to the development of biologic therapies targeting specific molecular mechanisms involved in the process of the disease, and a significant expansion of treatment horizon in these patients. The biologic therapies for metastatic renal cell carcinoma belong to two main groups: angiogenesis inhibitors (VEGF-R inhibitors like sunitinib, sorafenib, pazopanib and axitinib), and inhibitors of the mTOR protein (everolimus and temsirolimus). These biologic therapies led to a significant improvement in the patients' survival. Nonetheless, these therapies are associated with a unique profile of side effects like hypertension, mucositis, and hand-foot syndrome with VEGF-R inhibitors therapy, and non-infectious pneumonitis with mTOR inhibitors therapy. The present review will focus on the modern approach to metastatic renal cell carcinoma.