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This longitudinal study examined the causal relationships between job demands, job control and supervisor support on the one hand and mental health on the other. Whereas we assumed that work characteristics affect mental health, we also examined reversed causal relationships (mental health influences work characteristics). Further, the topic of the appropriate time lag for testing causal relationships was addressed. Our hypotheses were tested in a 4-wave study among a heterogeneous sample of 668 Dutch employees using structural equation modelling. The results provide evidence for reciprocal causal relationships between the work characteristics and mental health, although the effects of work characteristics on well-being were causally predominant. The best model fit was found for a 1-year time lag. Compared to earlier—predominantly cross-sectional—results, the present study presents a stronger case for the effects of work characteristics on the development of strain. The results also emphasize the need for a dynamic view of the relationship between work and health; the one-directional viewpoint in many work stress models does not seem to fully capture the relations between work characteristics and well-being.