Continuous-flow left ventricular assist devices reduce short-term mortality and improve quality of life in patients with end-stage heart failure. Unfortunately, device-related complications remain common, with many patients experiencing adverse events within the first year. New literature suggests that rates of device-related thrombosis may be increasing since 2011, which is particularly troublesome given that this pathology can result in a disabling stroke, organ damage, and death. In 2013, a group of practitioners in the field of mechanical circulatory support published a treatment algorithm based on their expert opinion. However, a comprehensive review of the pharmacotherapy of this condition is lacking. A search of the literature revealed 20 separate publications of case reports or case series describing outcomes associated with the use of drug therapy for suspected pump thrombosis. Each of these experiences was limited by small sample size, nonrandomized treatment allocation, and nonstandardized medication dosing. Data describing the outcomes of surgical versus medical management of device thrombosis are also sparse, with only three published reports identified. Based on the review of this limited literature, surgical management appears to be the preferred treatment modality, especially in those with organ hypoperfusion or hemodynamic instability. In patients ineligible for surgery, pharmacotherapy options remain limited. Use of all drug classes described in the literature for the HeartMate II device—fibrinolytics, glycoprotein IIb/IIIa inhibitors, and direct thrombin inhibitors—was hindered by either marginal efficacy or bleeding. Based on historical experience with unfractionated heparin in patients under HeartMate II support, we recommend this agent as a possible option for those with suspected pump thrombosis in lieu of surgical device exchange. For the HeartWare HVAD, limited data suggest that direct intraventricular administration of alteplase may be an acceptable treatment alternative. Additional research is clearly needed to further delineate the role of pharmacotherapy and to identify the optimal agent for managing this potentially life-threatening condition.