The recent application of antiangiogenic therapies has opened a new corridor of treatment in metastatic renal cell carcinoma. These therapies influence intracellular pathways that are important in angiogenesis and tumor progression. Although each of these agents produces objective responses as well as progression-free survival benefits, durable complete responses have not generally been observed, and thus, resistance to these chronic therapies is almost universal. The increasing use and eventual resistance to these agents has defined an increasing population of patients with targeted therapy-refractory disease. However, there are limited clinical and preclinical data to guide treatment decisions for these patients. This review will examine the existing data in this setting, describe ongoing clinical investigations, and discuss challenges unique to this patient population.