Interferon-gamma (IFN-γ) is a pleiotropic cytokine with antiproliferative, pro-apoptotic, and antitumor mechanisms. Despite its broad evidence in tumor immune surveillance, IFN-γ-based therapies have shown limited success in clinical trials. Recent studies suggest that IFN-γ may also play a protumorigenic role through mechanisms such as insensitivity to IFN-γ signaling, downregulation of major histocompatibility complexes, and upregulation of indoleamine 2,3-dioxygenase and checkpoint inhibitors. However, IFN-γ-mediated responses are still positively associated with patient survival in several cancers. This review discusses the current knowledge on the pro- and antitumorigenic effects of IFN-γ, highlighting the importance of identifying IFN-γ-responsive patients to improve therapies that exploit associated signaling pathways. The review covers the canonical signaling and regulatory mechanisms of IFN-γ, its actions on immune cells and transformed cells, and its role in cancer. It also explores the dual face of IFN-γ in tumor immunity, where it can both promote tumor immune surveillance and support tumor escape. The effectiveness of future IFN-γ-based therapies will likely depend on the development of systems to deliver the appropriate amount of cytokine to target cells, minimizing toxicity and maximizing therapeutic outcomes.Interferon-gamma (IFN-γ) is a pleiotropic cytokine with antiproliferative, pro-apoptotic, and antitumor mechanisms. Despite its broad evidence in tumor immune surveillance, IFN-γ-based therapies have shown limited success in clinical trials. Recent studies suggest that IFN-γ may also play a protumorigenic role through mechanisms such as insensitivity to IFN-γ signaling, downregulation of major histocompatibility complexes, and upregulation of indoleamine 2,3-dioxygenase and checkpoint inhibitors. However, IFN-γ-mediated responses are still positively associated with patient survival in several cancers. This review discusses the current knowledge on the pro- and antitumorigenic effects of IFN-γ, highlighting the importance of identifying IFN-γ-responsive patients to improve therapies that exploit associated signaling pathways. The review covers the canonical signaling and regulatory mechanisms of IFN-γ, its actions on immune cells and transformed cells, and its role in cancer. It also explores the dual face of IFN-γ in tumor immunity, where it can both promote tumor immune surveillance and support tumor escape. The effectiveness of future IFN-γ-based therapies will likely depend on the development of systems to deliver the appropriate amount of cytokine to target cells, minimizing toxicity and maximizing therapeutic outcomes.