Immunotherapy confers a small but significant overall survival advantage in metastatic renal cell carcinoma (RCC) but only for the minority of patients, i.e. the 20% with good prognostic features. Recent developments in the molecular biology of renal cell carcinoma have identified multiple pathways associated with the development of this cancer. Several strategies have been investigated targeting these pathways, with significant clinical benefits shown in early studies. New agents including the small molecule targeted inhibitors sunitinib, sorafenib and temsirolimus, and the monoclonal antibody bevacizumab have shown anti-tumour activity in randomised clinical trials and have become the standard of care for most patients. Sunitinib and temsirolimus have shown significant improvements in progression-free survival (sunitinib) and overall survival (temsirolimus) in separate phase III studies in the first-line setting when compared with interferon-alpha. Sorafenib has demonstrated prolonged progression-free survival in a phase III study in comparison with placebo in the second-line setting. More recently two phase III studies have compared bevacizumab and interferon-alpha with interferon-alpha alone. Both studies showed a statistically significant improvement in progression-free survival for the combination arm. Additional studies are needed to optimise the use of these agents by identifying those patients who most benefit and elucidating the best way of delivering them, either in combination or as sequential single agents.