Monoclonal antibodies (mAbs) can significantly improve patient outcomes in cancer treatment while reducing related side effects, offering a targeted therapy alternative to traditional treatment regimens. This chapter describes the development, mechanisms, and applications of mAb therapies as critical components of cancer immunotherapy. The chapter covers the history and progression of the use of mAbs in therapy, their multiple mechanisms—such as immune checkpoint inhibitors, the acumen for cancer antigens and antibody—drug conjugates—and the newest developments in this area. Moreover, this chapter reviews relevant case studies and trial data to compare the impact of these agents on various malignancies. This chapter concludes with a summary of the current challenges—developed resistance, on the one hand—and toxic side effects, e.g., cytokine release syndrome and neurotoxicity, on the other—and prospective avenues of the field.