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Seven small molecular weight targeted agents have been approved for the treatment of metastatic renal cell carcinoma (mRCC), includ-ing the humanised anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (used in combination with interferon [IFN]-a); the multi-targeted receptor tyrosine kinase inhibitors (TKIs) sunitinib, pazopanib, axitinib and sorafenib; and the mammalian target of rapamycin inhibitors (mTORIs) everolimus and temsirolimus. According to the results of comparative clinical trials of sunitinib and pazopanib (COMPARZ and PISCES), pazopanib has more preferable safety profile due to elimination of the risk of hepatic complications. However, 20-25% of patients do not respond to the first-line therapy. The treatment strategy for this group of patients is to select optimal treatment sequence. The robust clinical data confirm the advantage of consecutive usage of targeted agents in patients with mRCC, explaining the improved response with lack of cross-resistance. Currently, everolimus is an optimal choice in the second-line targeted therapy for mRCC since it has high-level evidence of its efficacy and at the same time it allows to overcome resistance to the anti-angiogenic therapy. Currently, there are no sufficient data on the effectiveness of the targeted agents in the third-line setting.