The process of toxicological analysis of postmortem specimens can reveal some special difficulty compared to the clinically derived specimens. Many drugs are not stable and the chemical changes that occur in the specimens, due to the hydrolysis processing, the time passed, the drug metabolism, and matrix effect, even when the postmortem interval is short, may affect the interpretation of the toxicological results. This interpretation may be critical, not only to the thorough investigation of different kind of forensic cases, but also to clinical or other cases as it provides very significant challenges to the scientists. This article reviews (a) particular toxicological issues associated with some toxic substances responsible for common lethal or nonlethal poisonings, such as opiates, cannabis, and cocaine and the vast number of factors that affect drug concentration; and (b) focuses on toxicological issues associated with the analytical findings of certain postmortem specimens. The toxic substances cited in the present paper are the most commonly found in forensic cases in Greece. The investigation of these drug-related deaths has revealed that heroin, alone or in combination with other psychoactive substances, such as cannabis and cocaine, is the main drug involved in these deaths.