For over 200 years, Western courts have considered pleas of “not guilty by reason of insanity” (NGRI) for defendants in possession of a mental defect rendering them unable to understand the wrongfulness of their act. Until recently, determining the mental state of a defendant has fallen largely upon the shoulders of court psychologists and experts in psychiatry for qualitative assessments related to NGRI pleas and mitigation at sentencing. However, advances in neuroscience—particularly neurological scanning techniques such as magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), computed tomography scanning (CT), and positron emission tomography scanning (PET)—may provide additional, pertinent biological evidence as to whether an organically based mental defect exists. With increasing frequency, criminal defense attorneys are integrating neuroimaging data into hearings related to determinations of guilt and sentencing mitigation. This is of concern, since not all brain lesions and abnormalities indicate a compromised mental state that is relevant to knowing whether the act was wrong at the time of commission, and juries may be swayed by neuroscientific evidence that is not relevant to the determination of the legal question before them. This review discusses historical and modern cases involving the intersection of brain lesions and criminality, neuroscientific perspectives of how particular types of lesions may contribute to a legally relevant mental defect, and how such evidence might best be integrated into a criminal trial. Copyright © 2009 John Wiley & Sons, Ltd.