Introduction: Radiation Induced Bystander Effect (RIBE) which causes radiation effects in non-irradiated cells has challenged the principle according to which radiation traversal through the nucleus of a cell is necessary for producing biological responses. What is the MECHANISM of this phenomenon? To have a better understanding of this rather ambiguous concept substantial number of original and reviewed article were carefully examined.Results: Irradiated cells release molecules which can propagate in cell environment and/or transmit through gap junction intercellular communication. These molecules can reach to non-irradiated cells and transmit bystander signals. In many investigations, it has been confirmed that these molecules are growth factors, cytokines, nitric oxide and free radicals like reactive oxygen species (ROS). Transmission of by stander signal to neighboring cells persuades them to produce secondary growth factors which in their turn cause further cell injuries. Some investigators suggest, organelles other than nucleus (mitochondria and cell membrane) are the origin of these signals. There is another opinion which suggests double strand breaks (DSB) are not directly generated in bystander cells, rather they are due to smaller damage like single strand breaks which accumulate and end up to DSB.Although bystander MECHANISMs have not been exactly known, it can be confirmed that multiple MECHANISMs and various pathways are responsible for this effect. Cell type, radiation type, experimental conditions and end points identify the dominant MECHANISM.Conclusion: Molecules and pathways which are responsible for RIBE, also cause systemic responses to other non-irradiation stresses. So RIBE is a kind of systemic stress or innate immune responses, which are performed by cell microenvironment. Irradiated cells and their signals are components of microenvironment for creating bystander effects.