Health care-associated infection remains a major issue of patient safety. It complicates a significant proportion of patient care deliveries, adds to the burden of resource use, and contributes to unexpected deaths. Early infection control pioneers showed that surveillance and prevention programs can be successful and have set the scene for today's infection control activities. Parameters for success include those to recognize and explain health care-associated infections and implement interventions to decrease infection rates and limit antimicrobial resistance spread. Current major challenges facing infection control programs are reviewed with an emphasis on recent trends in health care delivery systems, together with some vision on future activities and interactions toward such changes. Benchmarking of infection rates is considered inevitable, and, thus, surveillance strategies, adapted to changing health care systems, should improve and emphasize intervention and standardization. Major challenges for the future include antimicrobial use and control of resistances, new materials, emerging pathogens, infection control issues related to transgenic therapy, massive and complete immunosuppression and xenotransplantation, prion diseases, use of fully computerized patient record and data-mining-derived epidemiology, development of evidence-based recommendations for infection control and prevention, addressing cost constraints and newly apparent health care system trends, and health care worker behavior modification.