In the not so distant past, it was believed that for some reason, the immune system fails to recognize a tumor, allowing it to develop and grow. However, in this century the first indications appeared that the immune system actually does recognize tumor cells from the very early stages of tumor development but that for some reason, it tolerates them and allows them to develop. This phenomenon was described as the three-phasic process known as cancer immunoediting. Thus, it has been shown and recognized that tumor-induced tolerance is actually responsible for the immune system “failure” when immunosurveillance is concerned. However, these discoveries led to the development of a number of significant immunomodulatory therapies such as immunotherapy and novel, unconventional radiotherapy approaches aiming to overcome and brake tumor tolerance. This chapter will introduce and discuss the latest advances in modern radiation-immuno-oncology highlighting the interplay between tumor cells, radiation, and peritumoral immune microenvironment.