In this paper we will explore how the action of signs underlying all human experience precludes the possibility that we are being systematically deceived in our perception of reality. The simulation hypothesis, as well as similarly motivated skeptical scenarios, such as the brain-in-a-vat hypothesis and Descartes’ evil demon thought experiment, wrongly presuppose a modern, dualistic theory of knowledge, as well as a neuroreductionist model of sensation. However, we will see how the action of signs in human cognition presupposes the existence of a relational mode of being, namely, esse intentionale (“intentional being”), which is immaterial and incapable of subjection to technological manipulation. Furthermore, sensation, the origin of all human knowledge, and ens primum cognitum (“being as first known”), the condition of all human knowledge, both defy materialistic explanations. The doctrine of signs, as masterfully articulated by John Poinsot (John of St. Thomas), recognizes the triadic nature of relations underlying the full range of human experience. A proper understanding of the relationship between mind and world, as well as a recognition of the mistaken presuppositions underlying much of modern philosophy, will help to disillusion those who are convinced by the simulation hypothesis and other similarly motivated skeptical scenarios.