Evidence-based clinical practice guidelines encapsulate current knowledge to guide health care professionals in the treatment of patients with unstable angina or non-ST-segment-elevation myocardial infarction (NSTEMI), yet adherence to guideline recommendations is suboptimal. Guideline adherence may be improved by quality improvement programs such as the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation?) National Quality Improvement Initiative of the American College of Cardiology-American Heart Association Guidelines. The CRUSADE data have been analyzed to demonstrate that overall guideline adherence is directly associated with mortality and that improvement in guideline adherence saves lives. Also, the CRUSADE data have determined that the real-life mortality risk associated with unstable angina and NSTEMI is greater than suggested by clinical trials. The newer antiplatelet drugs recommended in early intervention and discharge treatment strategies are underused across many segments of the unstable angina-NSTEMI population. Glycoprotein IIb-IIIa inhibitors are underused in high-risk populations, and clopidogrel is markedly underused in patients who are medically managed rather than undergoing percutaneous coronary intervention or coronary artery bypass graft surgery. In addition, often the specialty of the treating physician and the status of the hospital influence the use of antiplatelet therapy. The reasons for underprescribing of antiplatelet drugs by physicians are not entirely clear but may be related to a lack of guideline familiarity and understanding, as well as factors such as drug novelty, safety, and cost. Continued education and data dissemination are therefore vital in promoting the prescription of guideline-recommended drugs, both in the early hospitalization phase and as patients transition to community-based care. The role of the pharmacist is pivotal in ensuring adherence to clinical guidelines by interacting with both the physician and patient.