Artifacts (misleading signs) are an inherent part of postmortem toxicology that needs to be assessed and managed, if possible. It is essential to be aware of and be able to identify artifcts. This review attempts to highlight the more important ones as far as known. There are several unique challenges with specimens collected for postmortem toxicology investigation. A major issue is a determination that includes an understanding of the drug use in the immediate antemortem setting and of the medical history contributing to pharmacokinetic variability. Analytical results may be biased by clandestine manufacture of drugs, treatment during resuscitation or hospitalization, as well as by the presence of tolerance. Drug concentration is likely to change already during the prefinal phase. The potential for postmortem alterations must be considered for all but a few drugs. They are likely to depend on a number of variables, including the drug's physicochemical and pharmacokinetic properties, and environmental conditions. The extent of these changes varies significantly between drugs. The phenomenon of postmortem redistribution can result in anatomical site differences as well as in changes over time. Body fluids and tissues as well as drugs present in these specimens are severely affected by autolysis (cell disruption) and putrefaction. As a result, degradation as well as formation of new entities as competing processes to postmortem redistribution occurs. Analysis of formalin‐fixed or embalmed samples may create problems with regard to the isolation of a drug along with a substantial loss, decomposition, or methylation of compounds. The main collection artifact is contamination. An appreciation of how contaminants may be introduced is important. Poor sampling will severely affect a case investigation. The use of appropriate specimen containers and preservatives can be critical with regard to ultimately identify a substance in an individual specimen. Fluoride preservation of blood is recommended for ethanol, cocaine, carbon monoxide, and cyanide. Addition of fluoride can, for example, inhibit neoformation of ethanol, whereas degradation of cocaine is only slowed. Precaution taken to preserve drug stability during storage until analysis is largely guided by the current knowledge on degradation mechanisms operating in a particular matrix. Problems may also occur during isolation and identification of a drug. Determination of the parent drug along with major metabolites and potential degradation products seems necessary to avoid misinterpretation.