Two conflicting phenomena, bystander effect and adaptive response, are important in determining the biological responses at low doses of radiation and have the potential to impact the shape of the dose-response relationship. Using the Columbia University charged-particle microbeam and the highly sensitive human-hamster hybrid (A_L) cells mutagenic assay, we show here that nonirradiated cells acquire mutagenesis through direct contact with cells whose nuclei have been traversed with a lethal dose of 20 alpha (α-)particles each. Pretreatment of cells with a low dose of X-rays 4 h before α-particle irradiation significantly decreased this bystander mutagenic response. Although adaptive response is largely protective in nature and the bystander response, in general, signifi es detrimental effects, the two processes share many common characteristics. There is evidence that extracellular signal-related kinase (ERK), nuclear factor-ΚB, cytokines, and mitochondrial functions play an important role in the bystander effects. However, all these signaling events are applicable to the adaptive response as well. These data suggest a common lineage between these two stress-related phenomena. A better understanding of how these two effects interact at the cellular, tissue, and organ levels will address some of the pressing issues on target size, radiation dose response, and, ultimately, low dose risk assessment.