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Air pollution is associated with a diversity of health effects, and evidence for a causal relationship with specific diseases exists. Exposure to air pollution is ubiquitous and typically beyond the control of the individual; the resulting health burden for the population can be high. Disproportionate effects are seen in individuals who have increased susceptibility to air pollution owing to individual- or community-level characteristics. As studies grow increasingly sophisticated, the understanding of who comprises the susceptible population continuously expands. Characteristics of susceptibility include genetic predisposition; socioeconomic factors; life stage; the presence of preexisting diseases, such as asthma, chronic obstructive pulmonary disease, cystic fibrosis; and the unique population of lung transplant recipients. This review explores how select populations, namely individuals with preexisting pulmonary disease and those living in communities of low socioeconomic status, have an increased susceptibility to the health effects of ambient air pollution. Genetic susceptibility, though a fundamental determinant of risk, is beyond the scope of this review and is not discussed. Strategies designed to mitigate air pollution-related health effects are discussed using a framework that addresses pollution exposure at multiple levels—government, state, community, and the individual. Emission reduction strategies remain the basis for public health protection; however, ancillary harm reduction measures are explored that can be adopted by susceptible communities and individuals.