Diethylene glycol (DEG), an extremely toxic chemical, has been implicated as the etiologic agent in at least 12 medication-associated mass poisonings over the last 70 years. Why DEG mass poisonings occur remains unclear. Most reports do not contain detailed reports of trace-back investigations into the etiology. The authors, therefore, conducted a systematic literature review on potential etiologies of these mass poisonings. The current available evidence suggests that substitution of DEG or DEG-containing compounds for pharmaceutical ingredients results from: (1) deception as to the true nature of certain ingredients by persons at some point in the pharmaceutical manufacturing process, and (2) failure to adhere to standardized quality control procedures in manufacturing pharmaceutical products intended for consumers. We discuss existing guidelines and new recommendations for prevention of these incidents.