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Even though a myriad of antimicrobial agents have been developed over the decades, resistant mechanisms continually break through, ultimately increasing our mortality and fears. Significant efforts have been made to evade these pathogenic resistances by developing novel antimicrobial agents which work on different targets. One possible, simple solution that has also been investigated has been to modify the counter-anion of cationic-based drugs. Although a multitude of studies have evaluated the efficacy of the active cationic agent, some have also explored the often-neglected influence of the counter-anion. Understanding the role of the counter-anions may provide new antimicrobial agents and an alternative approach to quell antimicrobial resistance. This review focuses on the various studies that have either directly or in-directly evaluated the role of the counter-anion on antimicrobial activities. Indeed, certain cationic-based agents display significant alternation in their activity when paired with the correct anion.