Non-clear cell renal cell carcinomas (RCCs) represent a heterogeneous group of diseases with distinct molecular drivers, histologies, and clinical outcomes. Their low incidence and heterogeneity have resulted in a lack of studies that address the optimal strategies for each subtype. This article (the second in a 2-part series) reviews the current targeted therapies approved for RCC, such as the vascular endothelial growth factor receptor tyrosine kinase inhibitors and the mammalian target of rapamycin inhibitors. Ongoing studies will provide more information regarding the role of these agents in non-clear cell RCC. Ultimately, enhanced understanding of genetic triggers and the development of more tailored treatments remain imperative to improve outcomes in non-clear cell RCC.