The introduction of molecular targeted therapies for patients with metastatic renal cell carcinoma has provided treatment options that are more efficacious and better tolerated than cytokine therapy, the previous standard of care. These advances have led to renewed efforts to define the health-related quality of life (HRQOL) impact of disease status stabilization or improvement versus that of treatment-associated adverse events. The distinct classes of targeted agents have unique AE profiles related to their specific targets; therefore, treatment considerations should include the patient's pretreatment HRQOL along with the known HRQOL effects of each drug. With more second- and third-line treatment options available for patients with metastatic renal cell carcinoma, HRQOL outcomes in earlier lines of therapy may guide treatment decisions for subsequent therapy, as poor HRQOL at therapy onset predicts poor survival. Both general and disease-specific instruments are used in clinical trials to reveal the impact of treatment on patient-reported outcomes. In this article, the common instruments used to assess HRQOL and the HRQOL outcomes observed in pivotal trials of targeted therapies are reviewed. Current data indicate that first-line therapy with sunitinib and first-line therapy in poor-prognosis patients with temsirolimus provide improved HRQOL compared with interferon-α. First- and second-line therapy with pazopanib and second-line therapy with everolimus and sorafenib maintained HRQOL levels similar to placebo, indicating that these agents do not worsen HRQOL. The HRQOL effects of bevacizumab plus IFN-α have not been reported. As new agents enter clinical investigation, HRQOL data can help determine their overall role in treatment.