Immune-system activity induces changes in animal behavior such as decreased food intake, decreased exploratory behavior, increased sleep, and impaired cognitive functioning. These changes are mediated by proinflammatory cytokines, and the administration of cytokines produces the same profile of behavior change as do infection and inflammation. Results demonstrating differential effects of immune-system activation depending on environmental contingencies and physiological states support the hypothesis that the behavioral effects of immune activity may be mediated by motivation. In this article, the author outlines the behavioral changes induced by immune-system activation and discusses evidence for a motivational analysis of immune-induced behavior change and the potential involvement of motivation in human sickness behavior.