Due to improved understanding of the tumor biology and immunology, cancer immunotherapy has rapidly developed as a promising strategy to treat various types of cancer and become the fourth most popular therapy after the conventional methods including surgery, radiotherapy, and chemotherapy. Immune checkpoint blockade (ICB) therapy played a vital role in cancer immunotherapy by interfering with various immunosuppressive mechanisms and utilizing the host’s immune system to kill tumor cells, including inhibitors of cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 receptor (PD-1), and programmed cell death receptor ligand 1 (PD-L1). In addition, the emerging immune checkpoint blockers like anti-LAG-3 and anti-TIM-3 antibodies also perform promising therapeutic roles in the treatment of cancer. Therefore, this chapter will introduce a variety of immune checkpoints, elucidate the underlying mechanistic aspects of the immune checkpoint pathways in tumors, and further show the successful applications of nanotechnology in combination with immune checkpoint therapy to improve the antitumor efficacy.