The current national ambient air quality standards for PM 2.5 are based on particulate matter (PM) mass. Although epidemiological research conducted in the last few decades has associated PM mass with both respiratory and cardiovascular diseases, the heterogeneous and inconsistent nature of these associations suggests that not all components of PM are equally toxic. The capability of ambient particles to generate reactive oxygen species (ROS), also called the ROS activity or the oxidative potential is proposed as an alternative metric for relating the PM concentrations with health effects. In this chapter, we discuss our work on the measurement of oxidative potential of ambient PM from various sampling campaigns in the United States. The core objective of this work was to identify the components of ambient PM and their emission sources, which are most responsible for inducing the ROS generation. The role of organic compounds in the oxidative potential of PM was assessed by their removal using thermodenuder and solid phase extraction techniques, while the contribution of metals was quantified with a chelation technique. A class of water-soluble organic compounds characterized by their strong hydrophobicity known as humic-like substances or HULIS, and transition metals (particularly Fe, Cu, and Mn) were identified as the major species driving the ROS generation mechanisms in ambient particles. However, our work shows that there are strong synergistic and antagonistic interactions among the HULIS components and transition metals. Limited source apportionment results revealed that biomass burning and secondary organic aerosol are the largest contributors to the oxidative potential in the southeastern United States. Further studies in this direction should help to develop useful insights on the origin of PM toxicity leading to a better assessment of the human health effects of ambient PM pollution.