The role of tumor-induced immune modulation in cancer progression is currently a focus of investigation. The signal transducer and activator of transcription 3 (STAT3) is an established molecular hub of immunosuppression, and its signaling pathways are classically overactivated within malignancies. This article will review STAT3 operational mechanisms within the immune system and the tumor microenvironment, with a focus on therapeutic strategies that may impact outcomes for patients with cancer.