The treatment of metastatic renal cell carcinoma (RCC) has changed dramatically with the introduction of targeted therapies against vascular endothelial growth factor and the mammalian target of rapamycin. Because patients with clear cell histology account for more than 80% of patients with RCC, little evidence is available on treating patients with non–clear cell histologies. Most clinical trials have excluded them from enrollment, except for a randomized study investigating temsirolimus. Many retrospective studies on the use of sunitinib, sorafenib, and temsirolimus in patients with non–clear cell histology have shown response rates ranging from 3.7% to 16%. Prospective studies in non–clear cell histologies are ongoing. Although response rates may not be as high as those in patients with clear cell histologies, targeted therapy may provide a clinically meaningful response. New investigational therapies are on the horizon for papillary RCC—the most-common non–clear cell RCC histology—targeting pathways specific to this histology, such as the c-MET pathway.