While epidemiological studies indicate an association between adverse health effects and ambient ultrafine particle concentrations in susceptible individuals, toxicological studies aim to identify mechanisms which are causal for the gradual transition from the physiological status towards patho-physiological disease. Impressive progress has been made in recent years when objectives changed from classical tests like lung function, etc. to endpoints comprising of particle induced oxidative stress, cell signaling and activation, release of mediators initiating inflammatory processes not only in the respiratory tract but also in the cardio-vascular system. Particularly, the large surface area of ultrafine particles provides a unique interface for catalytic reactions of surface-located agents with biological targets like proteins, cells, etc. However, toxicological studies are hampered by a number of imminent complications when simulating long-term exposure of humans in urban environments with inherited and/or acquired susceptibility (e.g., acute exposure studies at high concentrations either in human subjects or animal models). Yet, based on a conservative estimate results available begin to show an adverse health risk for susceptible individuals and support the epidemiological evidence.