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Toxin-antitoxin (TA) modules are small operons in bacteria and archaea that encode a metabolic inhibitor (toxin) and a matching regulatory protein (antitoxin). While their biochemical activities are often well defined, their biological functions remain unclear. In Type II TA modules, the most common class, both toxin and antitoxin are proteins, and the antitoxin inhibits the biochemical activity of the toxin via complex formation with the toxin. The different TA modules vary significantly regarding structure and biochemical activity. Both regulation of protein activity by the antitoxin and regulation of transcription can be highly complex and sometimes show striking parallels between otherwise unrelated TA modules. Interplay between the multiple levels of regulation in the broader context of the cell as a whole is most likely required for optimum fine-tuning of these systems. Thus, TA modules can go through great lengths to prevent activation and to reverse accidental activation, in agreement with recent in vivo data. These complex mechanisms seem at odds with the lack of a clear biological function., (© 2021 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)