OBJECTIVES: Monitoring is essential to safe anticoagulation prescribing and requires close collaboration among pathologists, clinicians, and pharmacists. METHODS: We describe our experience in the evolving strategy for laboratory testing of unfractionated heparin (UFH). RESULTS: An intrainstitutional investigation revealed significant discordance between activated partial thromboplastin time (aPTT) and antifactor Xa (anti-Xa) assays, prompting a transition from the former to the latter in 2013. With the increasing use of oral factor Xa inhibitors (eg, apixaban, rivaroxaban, edoxaban, betrixaban), which interfere with the anti-Xa assay, we adapted our protocol again to incorporate aPTT in patients admitted on oral Xa inhibitors who require transition to UFH. CONCLUSIONS: Our experience demonstrates key challenges in anticoagulation and highlights the importance of clinical pathologists in helping health systems adapt to the changing anticoagulation landscape.