Hand cleansing is the primary action to reduce health-care-associated infection and cross-transmission of antimicrobial-resistant pathogens. Patient-to-patient transmission of pathogens via health-care workers’ hands requires five sequential steps: (1) organisms are present on the patient’s skin or have been shed onto fomites in the patient’s immediate environment; (2) organisms must be transferred to health-care workers’ hands; (3) organisms must be capable of surviving on health-care workers’ hands for at least several minutes; (4) handwashing or hand antisepsis by the health-care worker must be inadequate or omitted entirely, or the agent used for hand hygiene inappropriate; and (5) the caregiver’s contaminated hand(s) must come into direct contact with another patient or with a fomite in direct contact with the patient. We review the evidence supporting each of these steps and propose a dynamic model for hand hygiene research and education strategies, together with corresponding indications for hand hygiene during patient care.