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Immunotherapy has become one of the greatest advances in medical oncology over the last century; however, the optimal application for the treatment of different types of cancer remains an active area of investigation. Modern immunotherapy strategies augment the immune system and ideally, permit durable tumor-specific immune memory to target and kill cancer cells. This era began when first immune checkpoint inhibitor, ipilimumab, was approved. In fact, several monoclonal antibodies that mediate the immune checkpoint receptors have provided the most clinically meaningful improvement for cancer patients to date. Checkpoint blockade as monotherapy has demonstrated some encouraging results, although some combination strategies appear to augment those responses and may be particularly effective when administered earlier in the course of disease. Additionally, we have also discussed previous and ongoing clinical studies testing individual or combination immunotherapy in cancer patients. Overall, the goal of this review is to provide a summary and current status of immune checkpoints and their inhibitors as therapeutic approaches of cancer immunotherapy and highlight promising future directions. Clinical Trials Registration Numbers: NCT00094653, NCT00257205, NCT01866319, NCT02142738, NCT02302807, NCT01903993, NCT02125461, NCT00732082, NCT01968109, NCT02061761, NCT02817633, NCT03489343, NCT04570839, NCT00298181, NCT00298168, NCT00876902, NCT03812328, NCT02812875, NCT04475523, NCT02768558, NCT02617589, NCT02039674, NCT02030834, NCT03545815, NCT03289962.