The Food Quality Protection Act and the 1996 amendments to the Safe Drinking Water Act are two of the most recent examples of legislation calling for protection of susceptible subpopulations. As regulatory deadlines draw nearer, controversies in scientific and policy arenas increase about incorporating susceptibility in risk assessment. The previously accepted working definition of “susceptibility” has already been called into question. Part of the controversy results from different disciplines conceiving of susceptibility in different ways. Understanding the conceptual differences embodied within definitions can provide a basis on which a revised working definition may be developed across disciplines. The purposes of this article are to describe the varying definitions of susceptibility, discuss the differing concepts incorporated in the definitions, and recommend ways in which susceptibility may be defined and framed to meet current risk assessment needs. The present analysis of definitions from the fields of ecology, biology, engineering, medicine, epidemiology, and toxicology revealed different emphases that relate to the underlying perspectives and methods of each field. It is likely that susceptibility will need to be formally defined for public policy purposes, but until that time, the use of more informal communication and decision-making processes is suggested to develop and utilize a new working consensus on the definition of susceptibility.