Cytokines are secreted signalling molecules with decisive effects on haematopoiesis, innate and adaptive immunity, and immunopathology. Interleukin (IL)-21 is a novel cytokine produced by activated CD4(+) T cells and natural killer T (NKT) cells. IL-21 is part of a family of cytokines which include IL-2, -4, -7, -9 and -15 that all share the common IL-2 receptor gamma chain (gamma(c)) in their individual receptor complexes. IL-21 receptor (IL-21R) is widely expressed on both myeloid and lymphoid cell lineages and IL-21 actions include co-stimulation of B cell differentiation and immunoglobulin (Ig) production, co-mitogen of T cells, and stimulation of NK and CD8(+) T cell cytotoxic function. Initially, IL-21 was recognized for its anti-tumour effects in several preclinical tumour models, warranting its currently ongoing clinical development as a cancer immunotherapeutic. More recently, IL-21 has been associated with the development of a panel of autoimmune and inflammatory diseases, where neutralization of IL-21 has been suggested as a potential new therapy. In this review, we will cover the latest discoveries of IL-21 as a cancer therapy and its implications in immunopathologies.