Management of heart and respiratory failure has improved in recent years in parallel with advancements in pharmacological interventions and organ transplant. The advent of mechanical alternatives to biological organs is a burgeoning area available to clinicians in a variety of scenarios, including short-term procedures (e.g., cardiopulmonary bypass), longer and acute management (e.g., percutaneous catheter pumps, extracorporeal membrane oxygenation), and semi-to-permanent therapies (e.g., ventricular assist devices and total artificial hearts). The paradigm shift over the last decades transitioned these technologies from “bridge” therapies toward “destination” therapies, with a resultant increase in clinical utilization. It is clear, however, that whilst mechanical circulatory and respiratory support (MCRS) devices can sustain life, damage to blood and its constituents and/or activation of cellular processes can negatively impact health. These adverse effects may be broadly related to blood exposure to high shear stress and/or interactions between biological and artificial materials or gas interfaces. Only through advances in MCRS to minimize blood damage will complications be overcome and mechanical devices attain their true potential.