Introduction: Sunitinib is a multi-target, anti-angiogenic tyrosine kinase inhibitor and a key molecule in the treatment of metastatic renal cell carcinoma (mRCC). Since it first demonstrated its efficacy ten years ago, overall survival of mRCC has more than doubled, in part due to sunitinib. In most recent years, progress has been made in the comprehension of its mechanism of action and resistance.Areas Covered: In this article, clinical trials involving sunitinib in kidney cancer have been reviewed, defining its different indications in metastatic and localized RCC. The rationale of sunitinib's efficacy, preclinical trials, past-clinical trials and ongoing clinical trials are summarized. Dose and scheme base are discussed, as the recommended dosage is frequently not well tolerated. Combination therapies appear to be toxic. Novel immunotherapies are changing the landscape of mRCC treatment and challenging sunitinib. Special attention has been paid towards cancer cell biology and immunity involved in treatment response.Expert Commentary: Sunitinib's place in the therapeutic arsenal is being redefined with the arrival of major challengers. Dosage and scheduling of sunitinib remains a major challenge.