Comorbidity of psychological and physical disorders is substantial. This article presents a broad theoretical framework for identifying factors that contribute to and maintain comorbid conditions. The authors propose heuristic models of how co-occurrences of psychological and physical disorders are developed and maintained. The models specify biological, behavioral, cognitive, and social pathways that may account for comorbidity. Although the authors' discussion of psychological disorders is limited to the role of affective disturbances (subclinical negative moods as well as mood and affective disorders), the pathways they identify are thought to contribute to co-occurrences of other psychological disorders and physical disease as well. The authors emphasize that pathways linking comorbid states are bi-directional and that operative pathways differ depending on the specific affective response, illness behavior, disease, or disease stage.