The availability of agents targeting the vascular endothelial growth factor or mammalian target of rapamycin [mTOR] pathways has provided new treatment options for patients with metastatic renal cell carcinoma (RCC). Based on the results of pivotal randomized clinical trials, specific recommendations have been established for management of these patients in first- and second-line settings. However, certain subgroups of patients may be excluded or under-represented in clinical trials, including patients with poor performance status, brain metastases, and cardiac or renal comorbidities, elderly patients, and those with non-clear cell histology. For these subpopulations, management recommendations have emerged from expanded access programs (EAPs), small phase II studies, retrospective analysis of clinical data, and expert opinion. This paper describes recommendations from an expert panel for the treatment of metastatic RCC in these subpopulations. The efficacy of targeted agents appears to be inferior in these patient subgroups relative to the general RCC population. Tyrosine kinase inhibitors (TKIs) and mTOR inhibitors can be administered safely to elderly patients and those with poor performance status, although dose and schedule modifications are often needed, and close monitoring and management of adverse events is essential. In addition to local surgical treatment and radiotherapy for brain metastases, systemic treatment with a TKI should be offered as part of multidisciplinary care.While there are currently no data from randomized trials, sunitinib has the greatest body of evidence, and it should be considered the first choice in patients with a good prognosis. Patients with an acute cardiac event within the previous 6 months, New York Heart Association grade III heart failure, or uncontrolled high blood pressure should not be treated with TKIs. In patients with mild or moderate renal failure, there are no contraindications to TKI treatment. TKIs can be administered to patients undergoing dialysis, but other, less nephrotoxic agents and other alternatives should always be considered.In managing RCC among patients with non-clear cell histology, sunitinib seems to be more effective than everolimus for the papillary subtype, but there are no clear data to guide treatment for other subtypes. In conclusion, individualized treatment approaches are needed to manage RCC in subpopulations that are underrepresented in registration clinical trials.