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Responsibility is a legal—not medical—construct. However, science can be useful in exposing faulty assumptions underlying current doctrine or practice, illuminating changes in practice or evidentiary standards to better effectuate the law’s animating purpose, and even suggesting updates to legal standards to account for modern understandings of functionalities of concern. This Article uses the science of delusions to assess the law regarding, and practice of establishing, criminal irresponsibility for defendants with psychosis. Over the last two decades, researchers from the cognitive sciences have compiled strong evidence that a host of cognitive and emotional impairments contribute to the origin and maintenance of delusions by impairing decision-making. This Article uses insights from those literatures to make three contributions. First, it analyzes current insanity standards and demonstrates their intimate relationship with rationality. It then argues that courts should consider evidence of any significant reasoning impairment, whether cognitive or emotional, as probative to sanity. Second, and more controversially, the Article explains how the reasoning impairments associated with delusions could bear upon a defendant’s incapacity to know, or her ignorance of, the wrongfulness of her criminal act. In assessing the latter, the Article argues that scientific research exposes as misguided the narrow test of actual knowledge currently employed in nine jurisdictions across the United States. Courts in these jurisdictions hold that a delusional defendant lacked knowledge of her act’s wrongfulness only if her delusion, had it been true, would have justified or excused her act. Instead, the science of persecutory delusions exposes the legal wrongfulness standard as inappropriate for populations with delusions and suggests that courts should consider excusing defendants whose delusions fall within the broad contours of a legal defense.