Alessandro Leonetti, Francesco Leonardi, Melissa Bersanelli, Sebastiano Buti Medical Oncology Unit, University Hospital of Parma, Parma, Italy Introduction: Renal cell carcinoma (RCC) represents 2%–3% of all cancers in adults, and its pathogenesis is mainly related to altered cellular response to hypoxia. Lenvatinib, a novel multitarget tyrosine kinase inhibitor (TKI), represents a therapeutic option, in combination with mammalian target of rapamycin (mTOR) inhibitor everolimus, for the treatment of metastatic RCC (mRCC).Aim: The objective of this article is to review the evidence about the treatment of mRCC with combination of lenvatinib plus everolimus.Evidence review: Phase I studies supported clinical activity of lenvatinib in mRCC. A randomized, Phase II, open-label, multicenter trial demonstrated the clinical efficacy of combination treatment with lenvatinib plus everolimus in patients with progressive mRCC after prior therapy with TKI. Median progression-free survival was improved by 9 months with the combination therapy compared to the single-agent everolimus, with an overall response rate of 43% for the experimental regimen. Lenvatinib plus everolimus appeared to be slightly less toxic than single-agent lenvatinib and more toxic than single-agent everolimus; grade 3–4 adverse events occurred in 71% of patients. Currently, lenvatinib plus everolimus has US Food and Drug Administration approval for its use in mRCC after failure of previous treatment with TKI.Conclusion: The combination therapy with lenvatinib plus everolimus might be a promising choice for second-line treatment of mRCC patients. Based on the results of the Phase II trial, it is possible to speculate that the combination therapy could be appropriate for patients with high disease burden or strongly symptomatic patients. Keywords: lenvatinib, everolimus, evidence-based review, renal cell carcinoma, RCC