Increased drug use is continuing to have a detrimental impact on mortality worldwide, with particular public emphasis and recognition of the opioid epidemic in Northern America. The postmortem investigation of suspected drug-related fatalities requires a careful consideration of all available case information and cannot rely solely on the interpretation of toxicology results. The pathologist should be cognizant of the many pitfalls of interpretive postmortem toxicology. Collaboration between forensic pathologists and toxicologists is essential. Approaches to autopsy, expected findings, and toxicologic considerations in the postmortem investigation of drug-related deaths are discussed in this chapter.