The paper reflects on the last 15years of experience in the field of mixtures risk assessment. It summarizes results found in various documents developed by the Agency for Toxic Substances and Disease Registry (ATSDR) of the weight-of-evidence (WOE) approach applied to 380 binary combinations of chemicals. Of these evaluations, 156 assessments indicated possible additivity of effects [=], 76 indicated synergism (greater-than-additive effects [>]), and 57 indicated antagonism (less-than-additive effects [<]). However, 91 combinations lacked the minimum information needed for making any assessments and, hence, were undetermined. The paper provides examples of the rationale behind some of the WOE decisions and discusses the importance of expert judgments in risk assessment evaluations. Examples are given regarding the importance of human variability in mixtures' ability to affect human health and regarding the dose versus effect relationships.