Over the last decade, left ventricular assist device (LVAD) implantation has emerged as an alternative treatment strategy in patients with advanced heart failure irrespective of their transplant eligibility. However, success and applicability of this therapy is largely limited by high complication rates associated with these devices. Although superior outcomes have been achieved with the second-generation continuous-flow LVADs, device-related infections continue to be a prevalent complication in this patient population and contribute significantly to the financial burden of this therapy due to an increased need for hospitalizations and surgical interventions. Patient selection, device design and LVAD-induced immune system dysfunction appear to be major risk factors for the development of device-related infections. Improvements in device design and better patient selection strategies, particularly with respect to identifying individuals with genetic susceptibility to device-related infections, may further reduce this prevalent complication and improve outcomes in patients with advanced heart failure.