Healthcare workers' hands are the most common vehicle for the transmission of healthcare-associated pathogens from patient to patient and within the healthcare environment. Hand hygiene is the leading measure for preventing the spread of antimicrobial resistance and reducing healthcare-associated infections (HCAIs), but healthcare worker compliance with optimal practices remains low in most settings. This paper reviews factors influencing hand hygiene compliance, the impact of hand hygiene promotion on healthcare-associated pathogen cross-transmission and infection rates, and challenging issues related to the universal adoption of alcohol-based hand rub as a critical system change for successful promotion. Available evidence highlights the fact that multimodal intervention strategies lead to improved hand hygiene and a reduction in HCAI. However, further research is needed to evaluate the relative efficacy of each strategy component and to identify the most successful interventions, particularly in settings with limited resources. The main objective of the First Global Patient Safety Challenge, launched by the World Health Organization (WHO), is to achieve an improvement in hand hygiene practices worldwide with the ultimate goal of promoting a strong patient safety culture. We also report considerations and solutions resulting from the implementation of the multimodal strategy proposed in the WHO Guidelines on Hand Hygiene in Health Care.