This paper provides perspective on the theme, variations in susceptibility to inhaled pollutants, and various subthemes of the symposium. Special attention is given to the need for refining our definitions of susceptible individuals as members of subpopulations in the context of the total population. This includes the need to consider both medically defined subpopulations as well as the extreme responders that are considered a part of the medically normal population. Note is made of our need to acquire information that is relevant to the recurring question: “Are reversible functional changes adverse health effects?” It is proposed that the answer to this question will likely come from increased research using multiple biological systems that extend from the molecular and cellular level to intact individuals, with the focus being on understanding the mechanisms of disease induction at exposure levels likely to be encountered by people. This research, and especially the integration of data from multiple biological systems and extrapolation among species, is likely to be aided by consideration of the delivered dose to critical molecules, cells, and tissues. Such information is essential input for establishing scientifically defensible National Ambient Air Quality Standards.