The mortality rate due to illegal drug use has increased substantially in recent years, and the forces underlying this trend are unknown. In this paper, we conduct a mixed-method study to start an investigation into the underlying causes. In the quantitative analysis, we examine the trend in detail for people aged 25–64 years old using U.S. Vital Statistics and mortality information from Denver, Colorado. In the qualitative analysis, we generate hypotheses for the trend with interviews of first responders in Denver, including paramedics, police, emergency room physicians, and staff at the Medical Examiner’s Office. The quantitative analysis: (a) confirms that the national drug-related mortality is increasing; (b) demonstrates that the trend is present across a wide range of drugs and is not specific to either cocaine, opioids, or stimulants; and (c) is concentrated among decedents with low education. This national pattern is mirrored in Denver. The qualitative interviews of first responders highlight four promising hypotheses to explain the quantitative pattern of results: (a) the increase in the number of released inmates in the general population; (b) the aging of the baby boom cohort; (c) the increase in polydrug use; and (d) an increase in the availability of prescription drugs. Future research is warranted to assess the relative plausibility of these four explanations, and develop information to inform policy and interventions to counteract the rise of drug-related mortality.