A variety of negative affective characteristics have been studied as risk factors for the onset and course of physical illness. Symptoms of anxiety, depression, and anger, related personality traits, and related diagnosable disorders have most often been studied one at a time in this research. Given well documented and substantial associations among anxiety, depression, and anger, and among symptoms, traits, and disorders, effects of any one affective risk factor on health outcomes could reflect (1) the specific characteristic assessed, (2) a related but unmeasured characteristic, or (3) a general and multi-faceted negative affective characteristic. Moving beyond the “one at a time” approach to negative affective risk factors is essential in the development and implementation of risk-reducing interventions. Empirically supported conceptual models of the domain of negative affective risk factors are an essential guide to measurement and quantitative analysis in psychosocial research on the role of these risk factors in the development and course of disease. This chapter reviews these conceptual, measurement, and analytic issues as considerations in the critical interpretation of prior studies and in the design of future research.