A large number of peptides with anticancer activities have been reported. Many of them were isolated from natural sources. A significant portion was developed from combinatorial library methods. Many of these peptides have direct anti-proliferative or pro-apoptotic activities on cancer cells; others may affect the tumor microenvironment directly or kill the tumor cells via hormonal or immunological modulations of the host. To affect intracellular targets, the therapeutic peptides must be able to get inside the tumor cells. Peptides have been developed to target cell surface receptors. Some of these peptides may affect the tumor cells directly. Some of them have been used as vehicles to deliver potent cytotoxic drugs or nanomedicines to the tumor cells. Research on cancer immunotherapy is bearing fruit over these past few years. There is a great interest to develop effective cancer vaccines and checkpoint blockade peptides. Several cancer therapeutic peptides have already been approved for clinical use and many more are undergoing preclinical and clinical development. It is expected that peptides will become increasingly important as oncologic drugs in the future. This chapter covers the discovery, optimization and application of anticancer peptides, as well as their current status of clinical use and development.