Systemic therapy for first-line metastatic renal cell carcinoma has evolved toward immune checkpoint blockade combinations incorporating a PD-1/L1 inhibitor along with CTLA-4 inhibition or VEGF-targeted therapy. The new treatment paradigm that integrates immunotherapy for treatment-naïve advanced metastatic renal cell carcinoma creates a new therapeutic challenge for clinicians including the optimal way to integrate multidisciplinary care involving surgery, radiotherapy, and application of contemporaneous systemic treatment in subsequent lines of therapy following discontinuation of combination therapy. We outline the available data for the multidisciplinary management of metastatic renal cell carcinoma, systemic therapy options in the post–immune checkpoint blockade setting, and novel therapies in development for advanced renal cell carcinoma. We provide practical considerations to assist clinicians in treatment choice and map future directions for progress.