A century has passed since the publication of William James's Principles of Psychology, yet most of the questions James raised about the relation between physiological events and molar psychological or behavioral processes, such as emotion, remain unanswered. The sluggish progress in capitalizing on physiological signals to address general psychological questions is due in part to shortcomings in the quantification of physiological signals in humans and, perhaps more important, to the way in which investigators have been thinking about the relation between physiological signals and psychological operations. In this article, we illustrate these points, and we provide a conceptual framework to foster research and analysis of psychological phenomena based on physiological signals. Psychological operations and physiological responses are defined in terms of configural and temporal properties, and psychophysiological relations are conceptualized in terms of their specificity (e.g., one-to-one versus many-to-one) and their generality (e.g., situation or person specific versus cross-situational and pancultural). This model yields four classes of psychophysiological relations: (a) outcomes, (b) concomitants, (c) markers, and (d) invariants. Finally, the model specifies how to determine whether a psychophysiological relation is an outcome, concomitant, marker, or invariant, and it describes important limitations in inferences of psychological significance based on physiological signals when dealing with each.