Currently, 7 targeted agents and the combination of nivolumab/ipilimumab have been approved as first-line therapy for mccRCC. Sunitinib and pazopanib are the most effective first-line options, especially in favorable- and indermediate-risk patients. Nivolumab/ipilimumab seem to be the preferred first-line therapy in poor-risk patients, although cabozantinib, temsirolimus, sunitinib and pazopanib are also recommended. HD IL-2 remains a reasonable first-line treatment option in selected, favorable-risk younger patients with good performance status. The combination of ICI/VEGF-TKI is currently underway. Combinations of pembrolizumab/axitinib, avelumab/axitinib, atezolizumab/bevacizumab and pembrolizumab/lenvatinib seem to introduce the mccRCC therapy in a new auspicious era.