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Clinical toxicology and post-mortem toxicology cover a broad scientific field with many opportunities and challenges. This Special Issue addresses the opportunities and challenges of detecting the exposure and intoxications of various (recreative) drugs and novel active psychoactive drugs. Currently, an increasing number of drugs have become widely available on the internet, posing questions surrounding how and where can we detect these agents and their metabolites in body fluids, as well as what the potentials and limitations of comprehensive and targeted toxicology screenings are in clinical and forensic toxicology cases. Also Special Issue addresses novel options for the clinical management of intoxicated patients, including the prevention of (re)absorption, the enhanced extracorporal elimination of drugs, and specific antidotes. In cases of post-mortem toxicology, how do we interpret drug levels in blood and tissues, as well as address challenges related to post-mortem redistribution and degradation?