We describe the case of a patient on continuous venovenous hemodiafiltration with atrial fibrillation with rapid ventricular response and hypotension requiring vasopressor use, which warranted digoxin therapy. In the absence of guidelines specifying appropriate digoxin dosing in patients undergoing continuous venovenous hemodiafiltration, anecdotal evidence-guided digoxin dosing was performed for this patient using plasma digoxin concentration-based therapeutic drug monitoring. We use this case to demonstrate the potential role of physiologically based pharmacokinetic modeling in assisting therapeutic decision making.