Management of organ failure has improved in recent years in parallel with advancements in interventions, including organ transplant, although the shortage of donor organs remains the rate-limiting step. 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., extracorporeal membrane oxygenation), and semi-to-permanent therapies (e.g., ventricular assist devices). A paradigm shift has recently effected a transition from “bridge” therapies toward destination therapies, with a resultant increase in clinical utilization. It is clear, however, that while mechanical circulatory and respiratory support devices can sustain life, damage to blood and its constituents, and/or activation of cellular processes, can negatively impact recovery and health. These adverse effects may be broadly related to blood exposure to high shear stress and/or interactions between biological and artificial materials. Only through advances in mechanical circulatory and respiratory support to minimize blood damage will complications be overcome and mechanical devices attain their true potential.