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The worldwide problem of microbial resistance has drawn utmost attention for medicinal chemists because of failure of currently available antimicrobial therapy against microbial infections. Therefore, there is an urgent need to develop novel antimicrobial agents with different mode of actions. In the search of better antimicrobial agents, different heterocyclic compounds have been explored and out of them piperazine derivatives have shown a broad spectrum of pharmacological activities like antibacterial, antifungal, antitubercular, anticancer, antiviral, antioxidant activities etc. This communication is focused on to review antimicrobial activities of different piperazine derivatives in detail and the valuable information provided in this manuscript may help in the drug design and development of better antimicrobial agents.