Management of poisoning is best accomplished when an accurate diagnosis is made and enhanced by attention to five major diagnostic criteria: history, clinical signs, clinical laboratory evaluation, lesions, and chemical analysis. Used properly, all of these factors allow for a better understanding of clinical poisoning. Although not all of these are possible for individual incidents, a systematic approach to support these criteria will bring a more useful assessment of risk and an accurate diagnosis. This article covers key principles of diagnostic toxicology and provides specific suggestions for clinical, laboratory, postmortem, and chemical testing to best suggest and confirm a toxicologic diagnosis.