Over the past several years, the dominant paradigm in drug development for metastatic renal cell carcinoma (mRCC) has been to more selectively and potently target moieties such as the vascular endothelial growth factor receptor. The effectiveness of this strategy appears to be nearing a plateau, however, underscoring the need for novel approaches. Vaccine-based therapies represent one such approach. Several distinct vaccines are currently being examined in mRCC, each using a distinct mechanism of action. For instance, the autologous dendritic cell vaccine AGS-003 uses patient-specific antigens derived from primary tumor tissue. In contrast, the poxvirus vaccine TG4010 produces an antigenic response to MUC1, a cell surface glycoprotein that reduces cell-cell interactions and thereby precludes contact inhibition. Other vaccines elicit a response to a broader spectrum of antigens-for instance, the vaccine IMA901 is based on 9 tumor-associated peptides identified from a novel biotechnology platform combining mass spectroscopy, microarray analysis of RNA expression, and immunogenicity assays. Herein, the current status of vaccine-based therapies for mRCC is described in detail. Furthermore, challenges to clinical implementation (eg, cost, optimal pairing with targeted agents, appropriate sequencing) are presented.