Ignaz Semmelweis and Florence Nightingale were instrumental in promoting hand hygiene to prevent infections in healthcare. Semmelweis, the pioneer of hand hygiene, observed and implemented handwashing protocols at Vienna General Hospital, reducing mortality rates from puerperal fever. Nightingale emphasized cleanliness in healthcare during the Crimean War, leading to lower mortality rates amongst troops. Both lay the foundation for modern infection control practices. Hand hygiene is crucial in healthcare today, with the World Health Organization’s Five Moments framework in place. Positive deviance, which focuses on individuals achieving exceptional hand hygiene compliance, is a promising solution. By empowering healthcare workers and promoting a culture of change, positive deviance can reduce healthcare-associated infections. Further research is needed to maximize its potential impact on patient safety.