During the past decades, a large body of evidence has revealed that cytokinebased immunotherapy can potently stimulate anti-tumor immune responses and are beneficial for cancer patients. IL-12 is recognized as a prototype cytokine that can induce type 1 (Th1/Tc1) anti-tumor immune responses. However, clinical trials using IL-12 as a single regime, or as a vaccine substance, have demonstrated limited effectiveness in the majority of cases. Recent evidence suggests that IL-12 induces T cell terminal differentiation/exhaustion and thus T cell responses could not be sustained to resulting in tumor rejection. Thus, evaluation of other novel cytokines such as IL-27 that has potent anti-tumor activity yet induces sustained immune responses is highly desired. In this book chapter, we will discuss the Yin and Yang aspects of IL-12 family of cytokines (i.e., IL-12, IL-23, IL-27 and IL-35) in cancer pathogenesis and immunotherapy.