Cancer is a worldwide medical problem with significant repercussions on individual patients and societies as a whole. In order to alter the outcomes of this deadly disease the treatment of cancer over the centuries has undergone a unique evolution. However, utilizing the best treatment modalities and achieving cures or long-term durable responses have been inconsistent and limited, that is until recently. Contemporary research has highlighted a fundamental gap in our understanding of how we approach treating cancer, by revealing the intricate relationship between the immune system and tumors. In this atmosphere, the growth of immunotherapy has not only forever changed our understanding of cancer biology, but the manner by which we treat patients. It's paradigm shifting success has led to the approval of over 10 different immunotherapeutic agents, including checkpoint inhibitors, vaccine-based therapies, oncolytic viruses and T cell directed therapies for nearly 20 different indications across countless tumor types. Despite the breakthroughs that have occurred in the field of immunotherapy, it has not been the panacea for all cancers. With a deeper understanding of the immune system we have been able to peer into tumor immune escape and therapy resistance. Simultaneously this understanding has paved the way for the investigation and development of novel immune system altering agents and combinatorial therapies. In this chapter we review the immune system and its intricate relationship with cancer, the evolution of immunotherapy, its current landscape, and future directions in the context of resistance mechanisms and the challenges faced by immunotherapy against cancer.