Radiation-induced lymphopenia (RIL) is characterized by a significant decrease in the absolute number of lymphocytes circulating in the blood after radiotherapy. With the major shift in cancer management initiated by cancer immunotherapy (IT), the reduction of incidence of RIL appears today as an extremely promising way of potentiating the synergy between radiotherapy and immunotherapy. However, the causes of RIL and mechanisms involved are still poorly understood. Improving our knowledge on RIL is therefore essential to limit it and thus improve the quality of care delivered to patients. The objective of this review is to provide a global view of RIL from a clinical point of view, with particular emphasis on recent knowledge and avenues explored to explain RIL and especially its depletion and remission kinetics. An opening on treatment concepts to be rethought is conducted in the context of combined RT/IT treatments.