Immune checkpoint inhibitors (ICIs) are a relatively novel group of drugs that target and block specific molecules expressed on various types of cells, called immune checkpoints. These are involved in the immune response and are vastly found in immune cells and cancer cells, but also in other cell types. Immune checkpoint activation in cancer is linked to decreased antitumor response and dampened immune function. Thus, relieving this “break” on the immune system may enhance the body’s reaction against the tumor – a premise on which many therapeutic agents have been developed in the last couple of decades that have shown and continue to show remarkable results in cancer immunotherapy. The first representative of ICIs was ipilimumab, an anti-CTLA-4 monoclonal antibody, first used in advanced melanoma and approved by the FDA in 2011, which kickstarted the immunotherapy era. Since then, many ICIs have been developed and investigated, and as of November 2023, PD-1 and PD-L1 inhibitors and anti-CTLA-4 monoclonal antibodies are the only two groups of ICIs approved for monotherapy, as well as for use in combination with other antineoplastic drugs. Additionally, a LAG-3 inhibitor was recently approved by the FDA for combinational use with a PD-1 inhibitor to treat advanced melanoma. Other therapeutic agents targeting various immune checkpoints are being tested in preclinical and clinical trials, some showing promising results. Novel therapies involved in clinical trials include LAG3, TIM3, BTLA, TIGIT, VISTA, CD200R/CD200, CD73, adenosine A2A receptor, etc. Trials evaluating the use of already available immunotherapeutic agents in combination with other treatment modalities, such as target therapy, for various cancers are also under active investigation. This chapter summarizes some prominent immune checkpoint pathways, their receptors, ligands, and roles in the clinical setting, along with successful and pivotal studies of ICIs and ongoing research on investigational agents.