Simple SummaryThe advent of immune checkpoint inhibitors has dramatically changed the history of advanced renal cell carcinoma treatment. Their use in first-line therapy provides an undeniable advantage in terms of survival; nevertheless, a considerable proportion of patients undergo disease progression. Similarly to other advanced solid tumors, even in renal cell carcinoma, preliminary data are beginning to emerge concerning the activity and the efficacy of a rechallenge of an immune checkpoint inhibitor-based treatment. In this mini-review, we summarize available data about immunotherapy rechallenge in renal carcinoma and its future perspectives.AbstractImmune checkpoint inhibitor-based therapies represent the current standard of care in the first-line treatment of advanced renal cell carcinoma. Despite a clear benefit in survival outcomes, a considerable proportion of patients experience disease progression; prospective data about second-line therapy after first-line treatment with immune checkpoint inhibitors are limited to small phase II studies. As with other solid tumors (such as melanoma and non-small cell lung cancer), preliminary data about the clinical efficacy of rechallenge of immunotherapy (alone or in combination with other drugs) in renal cell carcinoma are beginning to emerge. Nevertheless, the role of rechallenge in immunotherapy in this setting of disease remains unclear and cannot be considered a standard of care; currently some randomized trials are exploring this approach in patients with metastatic renal cell carcinoma. The aim of our review is to summarize main evidence available in the literature concerning immunotherapy rechallenge in renal carcinoma, especially focusing on biological rationale of resistance to immune checkpoint inhibitors, on the published data of clinical efficacy and on future perspectives.