In recent years, an improved understanding of renal cell carcinoma (RCC) tumour biology has resulted in major advances in the treatment of patients with metastatic RCC (mRCC). Although immunotherapy with interleukin-2 and interferon-α was once the standard of care for mRCC, the introduction of novel agents targeting angiogenesis and signal transduction pathways has markedly improved patient outcomes. However, targeted agents rarely induce complete responses, and patients eventually develop resistance to therapy, prompting consideration of novel therapeutic approaches and a resurgence of interest in immunotherapy for RCC. Phase I/II trials of vaccination with allogeneic dendritic cell/tumour fusions in patients with mRCC have demonstrated immunological and clinical responses in some patients, and T-cell modulating agents (e.g. antibodies against programmed death 1 and cytotoxic T lymphocyte-associated antigen-4, or soluble lymphocyte activation gene-3) and dendritic cell-activating toll-like receptor agonists have also shown encouraging evidence of efficacy in early-phase clinical trials. These early studies suggest that immunotherapy may continue to be an effective approach for patients with mRCC. As such, a number of other strategies are currently under investigation, including adoptive cell transfer (ACT) with T cells modified to target proteins expressed by renal tumours such as MAGE-A3/12, DR4 and TRAIL, and ACT with autologous natural killer cells. Results from trials of novel immunotherapies are encouraging, with data from other indications helping to facilitate development. To realise the full benefit for patients, it is likely that immunotherapy will need to be combined with targeted agents or other agents. Novel therapies used in combination or sequentially have the potential to improve outcomes in mRCC, and results from ongoing/planned trials will shape future therapy.