Heroin overdose deaths in the Unites States more than tripled from 2010 to 2014, reaching almost 11,000 per year. Despite the use of the term “overdose,” many of these victims died after self-administering an amount of opiate that would not be expected to be fatal for these drug-experienced, and drug-tolerant, individuals. Various explanations of this overdose mystery have been proposed. I describe an explanation based on Pavlovian conditioning. Organisms associate cues present at the time of drug administration with the systemic effect of the drug. These drug-predictive cues come to elicit responses that attenuate the effect of a drug. Such anticipatory conditional responses mediate chronic tolerance. If the drug is administered in the presence of novel cues, tolerance fails to occur and the victim suffers an overdose. Overdose prevention strategies should incorporate information about the contribution of drug-associated cues to drug tolerance.