The epidemiological evidence for PM-associated health effects continues to mount. The effects, including morbidity and mortality, are most evident in the elderly and those with preexisting impairments in cardiopulmonary health. Recent preliminary field and controlled clinical studies support these associations by suggesting that PM can alter cardiac risk factors in a manner consistent with a higher risk of second heart attack. Empirical studies in healthy animals have provided evidence that PM and its emission surrogates cause lung injury, and perhaps more importantly these PM can exaggerate inflammatory, biochemical, hematologic, and physiologic impairments in animal models of cardiopulmonary disease. These findings have brought attention to the often underappreciated, integral structural and physiological interplay of the heart and lungs within the cardiopulmonary system, especially in conventional inhalation toxicology studies, if animal models are to enhance our understanding of PM health effects in humans, it is critical that we expand our knowledge of this interplay in both humans and animal models when the lung is challenged with PM or its copollutants. How PM modulates autonomic and other homeostatic functions of the cardiopulmonary system, particularly in those with preexisting impairments or heart-lung disease, will enhance our understanding of public health risks and the likely multiplicity of factors that determine the responsiveness of any individual.