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Targeted therapies have shown profound effects on the outcome of patients with advanced renal cell carcinoma (RCC). However, the optimal treatment for RCC of non-clear cell histology (nccRCC)—typically excluded from trials of targeted agents—remains uncertain.By carrying out extensive searches of PubMed and ASCO databases, we identified and summarised research into the biological characteristics, clinical behaviour and treatment of different histological subtypes of nccRCC, focusing on targeted therapy.The available data suggest that treatments currently approved for RCC are active in ncc subtypes, although the overall clinical benefit may be less than for clear cell RCC. Temsirolimus has proven benefit over interferon-alfa (IFN-α) in patients with nccRCC, based on phase III data, while everolimus, sunitinib and sorafenib have all demonstrated some degree of activity in nccRCC in expanded-access trials. No clear picture has emerged of whether individual histological subtypes are particularly responsive to any individual treatment.Further molecular studies into the pathogenesis of RCC histological subtypes will help direct the development of novel, appropriate targeted agents. Clinical trials specifically designed to evaluate the role of targeted agents in nccRCC are ongoing, and data from trials with sunitinib and everolimus will be reported soon.