Interferon (IFN)-gamma is the uppermost cytokine implicated in anti-tumor immunity. With its cytostatic, proapoptotic and immune-provoking effects, IFN-gamma plays a central role in the recognition and elimination of transformed cells. Considering well-characterized anti-tumor effects of this cytokine, many clinical trials and immunotherapy approaches have been designed to reinforce IFN-gamma-mediated immunity for different types of cancer. However, the outcomes were not satisfactory and leaded to questioning of alternative actions of IFN-gamma. Many regulatory pathways can be induced by IFN-gamma to protect the normal tissues from collateral damage and to facilitate the re-establishment of homeostasis. Nevertheless, malignant cells can take the advantage of IFN-gamma as an inducer of mediators inhibiting anti-tumor immune reactions. In addition, under the influence of tumor-derived factors, certain types of immune cells are also licensed by IFN-gamma to perform regulatory actions. This review focuses on the immune modulatory functions of IFN-gamma in cancer as an alternative story to be told. (C) 2016 Elsevier Ltd. All rights reserved.