Radiation therapy is one of the pillars of cancer treatment, with approximately one half of all cancer patients receiving it as part of their standard of care. Emerging evidence indicates that the biological effects of radiation are not limited to targeted cells. The radiation-induced bystander effect (RIBE) refers to the plethora of biological phenomena occurring in nonirradiated cells as a result of signal transmission from an irradiated cell. Experimental evidence has linked RIBE to numerous hallmarks of cancer including resisting cell death, tumor immune evasion, genomic instability, deregulated cellular energetics, tumor-promoting inflammation and sustained proliferative signaling as well as enhanced radioresistance, thus highlighting the potential role of RIBE events in patient treatment response. The mechanisms underlying RIBE events in vivo are poorly understood. However, elucidating the molecular mechanisms involved in their manifestation may reveal novel therapeutic targets to improve radiation response in cancer patients.