This article presents a case of first-degree murder for which the defendant was acquitted as not guilty by reason of insanity, based on a defense involving the concept of "settled insanity." The literature on settled insanity is reviewed and discussed in the context of voluntary and involuntary intoxication. Statute and case law from those jurisdictions in which settled insanity is specifically allowed as an acceptable threshold condition for the insanity defense define the concept as a permanent condition resulting from substance abuse, rather than the effects of intoxication, no matter how severe. Also discussed are potential criteria for this defense, including evidence that psychotic symptoms thought to be responsible for the crime were, in some manner, separate and apart from symptoms caused solely by voluntary acute intoxication. Other factors that may assist evaluators in differentiating settled insanity from the effects of acute intoxication are presented. It is recommended that evaluators attempt to determine the timing of the onset of psychotic symptoms in relation to substance abuse, the persistence of such symptoms beyond detoxification, and whether ongoing psychiatric treatment is necessary to ameliorate the symptoms beyond intoxication. In the case described, psychotic symptoms persisted long after acute intoxication and beyond the time when drugs or alcohol were detected in the accused's body, requiring clinical intervention for psychosis. Also, before the crime, the defendant had exhibited significant psychological difficulty. The evaluating clinician must still determine, even when a threshold condition is considered to be present, whether statutory criteria for the insanity defense (for the jurisdiction in which the crime allegedly took place) are met.