Patients with metastatic renal cell cancer (mRCC) have traditionally had poor responses to systemic therapies. Recent developments in molecular biology have increased our understanding of the oncogenic processes and pathways in clear-cell mRCC. The development of drugs that target these pathways has expanded treatment options, improved prognosis and changed standard management of patients with clear-cell mRCC. Sunitinib, sorafenib and pazopanib (oral tyrosine kinase inhibitors) as well as everolimus and temsirolimus (mTOR inhibitors) and interferon with bevacizumab (an antibody to VEGF) have improved patient outcomes in large Phase III trials. These drugs have been incorporated into standard practice. Sunitinib has been adopted as first-line standard of care. Many agents are in development for treatment of mRCC, including axitinib in Phase III trials. We will review these treatments, their toxicities and how these targeted agents have impacted on mRCC.