Non-clear cell renal cell carcinoma (nccRCC) is a broad term that refers to a diverse group of tumors, each with its own distinct biologic and therapeutic profile. The management of nccRCCs is often based on extrapolating data from clinical trials in the more common clear cell renal cell carcinoma, but our emerging prospective and retrospective clinical experience in nccRCC allows us to make more precise recommendations tailored to each histology. The systemic therapy options for metastatic nccRCC include targeted therapies such as tyrosine kinase inhibitors, immune checkpoint inhibitors, and, for specific rare subtypes, cytotoxic chemotherapy. Each nccRCC histology may respond differently to these regimens, which makes accurate pathologic diagnosis imperative. In the present review, we discuss the available clinical and biological data that can help guide systemic therapy recommendations for specific nccRCC subtypes.