Purpose of Review <p>This review critically examines the efficacy and safety of chlorhexidine gluconate (CHG), the gold-standard antiseptic for infection prevention. It aims to address concerns regarding CHG’s adverse effects, effectiveness against Gram-negative bacteria, and potential for resistance, distinguishing myths from evidence-based realities.</p> Recent Findings <p>CHG demonstrates unparalleled efficacy in reducing catheter-related bloodstream infections, particularly in alcoholic formulations. Reports of CHG-related allergies are rare, and adverse reactions are generally mild and manageable. Laboratory studies suggest mechanisms of microbial tolerance and resistance, including cross-resistance with antibiotics, but robust clinical evidence remains limited. Recent trials reinforce CHG’s broad-spectrum antimicrobial activity and highlight its role in reducing infections without significant drawbacks.</p> Summary <p>CHG’s safety and efficacy profile supports its continued use in infection prevention, with benefits far outweighing theoretical risks. Rational use strategies tailored to infection risk levels and ongoing resistance monitoring are essential to optimise its application in clinical practice.</p>