Recent studies have highlighted crosstalk between irradiated cells and non-irradiated bystander cells and have uncovered high-frequency phenotypes of genomic instability in the progeny of irradiated cells that cannot be solely explained by radiation-induced mutation. It is difficult to explain these multicellular and multi-generational phenomena using the current paradigm of radiation biology. Radiation-induced bystander effect is a type of multicellular response to radiation that illustrates that the unit of function in multicellular organisms is neither the genome nor the cell. Cell function in complex three-dimensional tissues is coordinated by soluble signaling peptides and by small molecules within the context of insoluble scaffolding provided by the extracellular matrix. Adaptive response and radiation-induced genomic instability could thus result from persistent signaling perturbations following radiation exposures. A model of radiation response based on the systems biology principles of network interconnectivity and spatial organization should reconcile the apparent contradiction of these cellular phenotypes within the higher order structure of tissues and organisms.