In 1996, the Agency for Health Care Policy and Research (AHCPR, now AHRQ, the Agency for Healthcare Research and Quality) released the first federal clinical practice guideline for smoking cessation that was updated in 2000 by the United States Public Health Service (USPHS). The innovative guideline identified six evidence-based strategies for healthcare systems to facilitate the institutionalization of tobacco dependence treatment so that smokers received evidence-based treatments as a routine part of health care. A growing body of evidence demonstrates the importance of systems approaches. This paper discusses the evidence for the systems-level strategies outlined in the guidelines, as well as future directions and needed systems-level research. Promising strategies include: (1) clinical systems organized to cue assessment of smoking status and assistance to smokers, (2) leveraging clinical information systems to provide performance feedback, (3) providing full insurance coverage for evidence-based cessation treatment, and (4) including tobacco-cessation treatment as a measured standard of care by national accreditation organizations. These systems-level approaches increase the likelihood that tobacco use is addressed systematically in the healthcare delivery system. Further research to optimize the effectiveness and adoption of these strategies will help ensure that patients receive evidence-based interventions that foster tobacco-use cessation.