Hand hygiene prevents cross-infection in hospitals, but compliance with recommended instructions often is poor among healthcare workers. Although some previous interventions to improve compliance have been successful, none has achieved lasting improvement. This article reviews reported barriers to appropriate hand hygiene and factors associated with poor compliance. Easy access to hand hygiene in a timely fashion and the availability of skin-care lotion both appear to be necessary prerequisites for appropriate hand-hygiene behavior. In particular, in high-demand situations, hand rub with an alcohol-based solution appears to be the only alternative that allows a decent compliance. The hand-hygiene compliance level does not rely on individual factors alone, and the same can be said for its promotion. Because of the complexity of the process of change, it is not surprising that solo interventions often fail, and multimodal, multidisciplinary strategies are necessary. A framework that includes parameters to be considered for hand-hygiene promotion is proposed, based on epidemiologically driven evidence and review of the current knowledge. Strategies for promotion in hospitals should include reasons for noncompliance with recommendations at individual, group, and institutional levels. Potential tools for change should address each of these elements and consider their interactivity.