Uncertainty regarding the sources and chemical/physical properties of particular matter (PM) responsible for adverse health effects remains, despite momentous research efforts. The ambitious 10 year US NPACT initiative is deemed to have made a valuable contribution to the policy arena by demonstrating that no particle components can as yet be conclusively ruled out as not having an effect on public health. Upon focusing on studies conducted in different regions of world, within air sheds that vary with respect to a PM composition, size and source the very complex issue of differential toxicity is reaffirmed. Not only are individual PM characteristics and sources associated with certain effects in some locations and not in others but also, strengths of associations between effects and individual chemical components of the ambient mix vary from one effect to another. To further our understanding so that we can definitively conclude, or otherwise, that additional indicators have a role in protecting public health more effectively than the targeting total PM mass, comparison and synthesis of existing data through systematic reviews and quantitative meta-analysis must continue. Future studies should embrace refined modeling techniques and PM speciation data, enhance individual and population indoor/outdoor exposure, incorporate specific disease categories and better define susceptible individuals. Regionally specific studies are also needed to predict the impact of effective and sustainable control strategies. Owing to future population growth and increased ambient PM2.5 concentrations, mortality from air pollution has been estimated to double by 2050—a statistic that calls for global air quality control measures, informed by sophisticated developments in research, and interpretation of the latter into region-specific clean air policies.