Counterfactual reasoning is a hallmark of human thought, enabling the capacity to shift from perceiving the immediate environment to an alternative, imagined perspective. Mental representations of counterfactual possibilities (e.g., imagined past events or future outcomes not yet at hand) provide the basis for learning from past experience, enable planning and prediction, support creativity and insight, and give rise to emotions and social attributions (e.g., regret and blame). Yet remarkably little is known about the psychological and neural foundations of counterfactual reasoning. In this review, we survey recent findings from psychology and neuroscience indicating that counterfactual thought depends on an integrative network of systems for affective processing, mental simulation, and cognitive control. We review evidence to elucidate how these mechanisms are systematically altered through psychiatric illness and neurological disease. We propose that counterfactual thinking depends on the coordination of multiple information processing systems that together enable adaptive behavior and goal-directed decision making and make recommendations for the study of counterfactual inference in health, aging, and disease.