Continuous-flow left ventricular assist devices (LVAD) have emerged as the standard of care for advanced heart failure patients requiring long-term mechanical circulatory support. Evidence-based clinical management of LVAD-supported patients is becoming increasingly important for optimizing outcomes. In this state-of-art review, we propose key elements in managing patients supported with the new continuous-flow LVADs. Although most of the presented information is largely based on investigator experience during the 1,300-patient HeartMate II clinical trial, many of the discussed principles can be applied to other emerging devices as well. Patient selection, pre-operative preparation, and the timing of LVAD implant are some of the most important elements critical to successful circulatory support and are principles universal to all devices. In addition, proper nutrition management and avoidance of infectious complications can significantly affect morbidity and mortality during LVAD support. Optimizing intraoperative and peri-operative care, and the monitoring and treatment of other organ system dysfunction as it relates to LVAD support, are discussed. A multidisciplinary heart failure team must be organized and charged with providing comprehensive care from initial referral until support is terminated. Preparing for hospital discharge requires detailed education for the patient and family or friends, with provisions for emergencies and routine care. Implantation techniques, troubleshooting device problems, and algorithms for outpatient management, including the diagnosis and treatment of related problems associated with the HeartMate II, are discussed as an example of a specific continuous-flow LVAD. Ongoing trials with other continuous-flow devices may produce additional information in the future for improving clinical management of patients with these devices.