Percutaneous coronary intervention (PCI) is the preferred reperfusion strategy in the management of patients with ST-elevation myocardial infarction (STEMI) and higher-risk patients with unstable angina/non-STEMI (UA/NSTEMI). Recent updates have been issued for guidelines from the American College of Cardiology and American Heart Association delineating the appropriate use of anticoagulants as ancillary therapies to PCI. This manuscript reviews the recent clinical trial data supporting the updated guidelines and highlights remaining areas of uncertainty. SCOPUS and Pubmed were searched for relevant English-language reports of clinical trials, registries, articles and case reports. Search terms included but were not limited to: PCI, anticoagulation, ancillary, STEMI, NSTEMI, angina, acute coronary syndrome. The reference lists of identified articles were searched for additional relevant publications. Unfractionated heparin (UFH), the historical standard of care for anticoagulation in STEMI and NSTEMI patients undergoing PCI, is sub-optimal and the list of anticoagulants recommended for alternatives in the current guidelines has expanded to include superior anticoagulants, including the low-molecular-weight heparin enoxaparin and the direct thrombin inhibitor bivalirudin. Additionally, fondaparinux is recommended if supplemented during PCI by an additional agent with anti-IIa activity. However, uncertainties in the guidelines remain. Clinical discretion is still required when deciding which anticoagulant to use, ensuring seamless transitions throughout the care pathway, and how to correctly identify the risk status of a patient and modify anticoagulant regimens accordingly, such as in special patient populations. The published evidence supports the updates to the guidelines. Updated guidelines still have knowledge gaps which require the application of clinical discretion by the cardiologist.