Renal cell carcinoma (RCC) is among the most resistant tumours to chemotherapy, radiotherapy and hormonal therapy. Cytokine therapy is effective in a small subset of patients, but it is associated with substantial toxicity and rarely benefits patients with extensive tumour burdens or adverse prognostic factors. Since 2005, clinical trials have shown significant clinical benefits for five molecularly targeted therapies in patients with advanced RCC. These agents constitute two mechanistic classes: (i) angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) ligand (bevacizumab, in combination with interferon-a) or VEGF receptors (sunitinib, sorafenib); and (ii) inhibitors of the mammalian target of rapamycin (mTOR) signalling (temsirolimus, everolimus). This review assesses the mechanistic distinctions and functional overlaps of these classes of agents, and discusses key characteristics of their respective clinical efficacy and side-effect profiles in patients with RCC, some of which might affect patient selection and treatment strategies. Current research is designed to optimize the use of these agents, as well as the development of new investigational therapies within these mechanistic classes. The differences and synergies are particularly important for understanding the best ways to integrate VEGF/VEGF receptor inhibitors and mTOR inhibitors for combination or sequential treatment of patients with advanced RCC.