The use of immunotherapy continues to improve the outcome of cancer patients, including those with advanced diseases. Interferon (IFN) therapy is the early immune approach, used in clinic to treat cancer patients with unresectable tumor or resistant to chemotherapy. IFN has been used for decades both in clinical and research settings as treatment for many types of cancer, including hematological malignancies and solid cancers. The antitumoral role of IFN has been demonstrated in both preclinical and clinical studies. However, some concerns regarding the immunosuppressive role of IFN and potential exacerbations of the disease have been also suggested and are currently under investigations. In the present chapter, we have attempted to evaluate the dual role of IFN in cancer and immunity. We have examined the three IFN types and evaluated their impact on the control or the promotion of cancer. The impact of IFN signaling within the tumor microenvironment appear critical in understanding the dual role of IFN, and ultimately developing novel immunotherapies.