Interleukin (IL)-27, a member of the IL-6/IL-12 heterodimeric cytokine family, was discovered by Kastelein and colleagues in 2002. It consists of Epstein-Barr virus-induced gene 3 and p28 subunits, and activates STAT1 and STAT3 through the IL-27 receptor formed by WSX-1 and gp130 subunits. IL-27 is a multifunctional cytokine playing critical roles in induction of the early signal for T helper (Th) 1 differentiation, inhibition of Th2 and Th17 differentiation, and suppression of pro-inflammatory cytokine production. Cytokines play critical roles in proper establishment of antitumor immunity. Among various cytokines, IL-12 has been most evaluated and shown to be one of the most effective cytokines in preclinical immunotherapeutic settings. Although IL-12 has a powerful antitumor activity against various tumors, IL-12 therapy has been limited by its systemic toxicities. Recent studies revealed that IL-27 exerts a potent antitumor activity against various tumor models such as colon carcinoma, neuroblastoma and melanoma via different mechanisms depending on the characteristic of each tumor. These include mechanisms through CD8⁺ T cells, natural killer cells, anti-angiogenic activity, and direct anti-proliferative activity. Therefore, IL-27 may be an alternative attractive candidate as a therapeutic agent to cancer immunotherapy.