The discussion here is divided into three parts. First there is a generic introduction to variability and uncertainty and a discussion of some underappreciated features of these concepts that have nontrivial implications for structuring risk analyses. Next are some suggestions for a way forward to build a better quantitative understanding of relevant variability and uncertainty. The process involves building databases of putative analogous cases to represent the concerns that are now reflected in the various point-estimate “uncertainty factors” or “adjustment factors” in the formulas used to derive current reference doses and reference concentrations (RfDs and RfCs). The use of such databases is illustrated with some limited selections from our own databases where some preliminary comparisons between child and adult population variability in activity and respiratory response parameters are possible. A final section reflects on the current evolution of practice in estimating variability in risk assessments.