Purpose: To focus on the use of targeted therapies against the non-clear histologic subtypes of renal cell carcinoma (RCC); papillary I and II, chromophobe, and collecting duct. The unique genetic and molecular profiles of each distinct non-clear kidney cancer subtype will be described, as these differences are integral to the development and effectiveness of the novel agents used to treat them. Materials and Methods: On the basis of MEDLINE database searches, we assessed all aspects of targeted therapy in non-clear cell RCC between 2000 and 2010. Trials focusing on non-clear RCC or those that treated clear cell tumors along with significant numbers of non-clear subtypes will be discussed. The role of cytoreductive nephrectomy and the use of neoadjuvant and adjuvant targeted therapy will be reviewed. Lastly, areas of future research will be highlighted. Results: The majority of clinical trials testing novel targeted therapies have excluded non-clear subtypes, providing limited therapeutic options for patients with these diagnoses and their oncologists. Conclusion: Patients presenting with advanced non-clear pathology should undergo a thorough metastatic evaluation and, if appropriate, surgical evaluation to determine if nephrectomy, lymphadenectomy, and/or metastectomy are warranted. Aggressive surgical extirpation is often recommended. Sunitinib also is adequately tolerated and oncologically active in subjects with non-clear histology.