In novel situations, where direct experience is lacking or outdated, humans must rely on mental simulations to predict future outcomes. This review discusses recent work on the neural circuits that support such inference-based behavior. We focus on two specific examples: 1) using knowledge about the associative structure of the world to infer outcomes when direct experience is lacking; 2) inferring the current value of options when the desirability of the associated outcome has changed since the original learning experience. These two examples can be studied in the sensory preconditioning and devaluation tasks, respectively. We review results from studies in animals and humans suggesting that the orbitofrontal cortex (OFC), together with the hippocampus and amygdala, is necessary for inference in both of these tasks. Together, these findings suggest that the OFC is a critical hub in the brain network that supports inference-based decision-making.