Ventricular assist devices (VADs) have played an important role in altering the natural history of end-stage heart failure. Low-grade hemolysis has been traditionally described in patients with VADs, indicating effective device functionality. However, clinically significant hemolysis could be crucial in terms of prognosis, calling for prompt therapeutic actions. The absence of solid and widely approved diagnostic criteria for clinically significant hemolysis, render the utilization of hemolysis laboratory markers challenging. Hemolysis incidence varies (5%-18%) depending on definition and among different VAD generations, being slightly higher in continuous-flow devices than in pulsatile devices. Increased shear stress of red blood cells and underlying device thrombosis appear to be the main pathogenetic pathways. No certain algorithm is available for the management of hemolysis in patients with VADs, while close clinical and laboratory monitoring remains the cornerstone of management. Imaging examinations such as echocardiography ramp test or computed tomography scan could play a role in revealing the underlying cause. Treatment should be strictly personalized, including either pharmacological (antithrombotic treatment) or surgical interventions.