Atrial fibrillation (AF) accounts for most embolic strokes, especially in elderly individuals. Although anticoagulation is known to reduce the risk of embolic stroke, a significant proportion of patients have relative or absolute contraindications to anticoagulation. The left atrial appendage has been implicated as the major source of emboli in more than 90% of ischemic strokes in nonvalvular AF. Left atrial appendage occlusion offers an alternative for stroke prevention in patients with an elevated stroke risk (CHADS2 score ≥2 or CHA2DS2-VASc score ≥3) who have a rationale for avoiding long-term oral anticoagulation after a shared decision-making process. However, there remain significant challenges in left atrial appendage occlusion therapy related to patient selection, the procedure itself, and postprocedural patient management decisions. In this review article, we discuss some of these challenges in a case discussion–based approach.