Epidemiological research has taught us a great deal about the health effects of airborne particulate matter (PM) particularly, cardiorespiratory effects of combustion-related particles. This has been matched by toxicological research to define underlying mechanistic pathways.To keep abreast of the substantial challenges that air pollution continues to throw at us, requires yet more strides to be achieved. For example, being aware of the most toxic components/sources and having a definitive idea of the range of associated disease outcomes. This review discusses approaches designed to close some of these knowledge gaps. These include a focus on particles arising from non-exhaust PM at the roadside and microplastics – both of which are becoming more relevant in the light of a shift in PM composition in response to global pressure to reduce combustion emissions. The application of hypothesis-free approaches in both mechanistic studies and epidemiology in unveiling unexpected relationships and generating novel insights is also discussed. Previous work, strengthening the evidence for both the adverse effects and benefits of intervention tell us that the sooner we act to close knowledge gaps, increase awareness and develop creative solutions, the sooner we can reduce the public health burden attributable to these complex and insidious environmental pollutants.