The field of transgenerational genomic instability in mammals, including humans, is a confusing area of contradictory results, generalizations based on limited data sets and confusion about terminology. This chapter will focus on radiation-induced effects on genome stability, with some discussion of the literature on chemical-induced effects where relevant. The old and recent radiation literature will be summarized, and controversial issues will be highlighted. The relevance of non-targeted effects, such as bystander signaling and stress-induced instability, will also be discussed. An emphasis will be placed on the recent data from the authors' laboratory concerning medium-and blood-borne signals, which appear to regulate behaviors of lower hierarchical levels to achieve coordination of tissue, organism and ecosystem response at higher levels of organization. The hypothesis is put forward that such signal-mediated coordination represents a natural response to stress such as radiation exposure, which enables an appropriate reaction to ensure an optimal outcome for irradiated organisms. Data sources will be reviewed, and limitations of these studies will be discussed. Most of the discussion will relate to experimental studies in (mainly) rodents, but available data on wild mammals (e.g., post Chernobyl) will also be discussed. © 2010 Nova Science Publishers, Inc. All rights reserved.