The proliferation of novel psychoactive substances (NPS) and the current opioid epidemic creates challenges for a toxicology laboratory. Methods capable of detecting and quantitating emerging compounds must be established despite limited information on toxicologically relevant concentrations. This paper will (i) describe how a publicly funded forensic laboratory reacted to the emergence of carfentanil as a public safety concern and (ii) contribute to the existing forensic literature by presenting a series of deaths involving carfentanil between July 2017 and June 2018. The Centre of Forensic Sciences is the primary provider of forensic toxicology testing in medicolegal death investigations in the province of Ontario. When carfentanil was first identified in the illicit drug supply, routine screening methods used by this laboratory were not sufficiently sensitive to detect the drug at concentrations expected in blood samples. Previously validated, multi-target liquid chromatography-tandem mass spectrometry (LC-MS-MS) quantitative methods already in use by the laboratory did show improved detectability for carfentanil. Thus, an existing LC-MS-MS method was adapted to include carfentanil, achieving improved sensitivity while also providing quantitation in suspected drug-related deaths. This approach had the added benefit that the LC-MS-MS method selected for modification was used in all death investigations requiring toxicology analysis in Ontario, thereby providing an opportunity for surveillance. Using this method, 4,953 cases were analyzed with carfentanil detected at a concentration greater than the limit of detection (0.05 ng/mL) in 160 decedents. Postmortem blood carfentanil concentrations ranged from less than 0.1 to 9.2 ng/mL. Of the 160 carfentanil-positive cases, 156 were classified as either mixed drug toxicity or carfentanil overdose. The approach described enabled this laboratory to efficiently implement a quantitative test for carfentanil in all death investigations, providing a useful template for modifying existing methods when a new psychoactive substance becomes available in the population.