Antibody-cytokine fusion proteins, also known as immunocytokines, comprise a novel class of biopharmaceuticals designed to localize immunomodulatory agents toward the tumor site and stimulate local immune cells to activate an anticancer response. The engineering of antibody-cytokine fusion proteins includes a broad variety of formats (e.g., full IgGs or antibody fragments), molecular targets (e.g., cell membrane antigens or extracellular matrix components), and different cytokine moieties, which need to be assembled to reach their correct targets and achieve an effective antitumor activity. Early preclinical studies hinted at the therapeutic potential of antibody-cytokine fusion proteins in several tumor models, but their application in clinical studies often resulted in complications associated with undesirable side effects or poor efficacy. These problems could be attributed to the pleiotropic activity of the cytokines and/or undesired off-target cell interactions that could not be compensated by the antibody affinity and specificity. A deeper understanding of the cytokine’s structure, interactions, and signaling is allowing the rational design of a new generation of immunocytokines with fine-tuned immune responses for safer and more effective cancer immunotherapy. The construction of new cytokine muteins fused to antibodies that are addressing many of the problems associated with the use of wild-type cytokines is transforming this field, and some of these novel immunocytokines are reaching clinical trials. This chapter presents the latest advances in the field of antibody-cytokine fusion proteins engineered with novel cytokine variants and their great potential for cancer therapy.