Each year, more than 20 million people with organ failure (OF) are admitted to intensive care units around the world.1 With a 30% mortality rate, it remains the leading cause of death in intensive care units. OF is preceded by 2 syndromes, the systemic inflammatory response (SIRS) and multiple organ dysfunction (MODS), which can progress throughout days or weeks to single or multiple OF and death.2 This patterned sequence is the feared sequelae of many inciting acute and critical diseases (ACDs), which include severe sepsis, hemorrhage, trauma, burns, acute pancreatitis, and most recently, SARS-CoV-2 infection.3 The heart, lung, and kidney organ systems are most at risk of failing. The failure to translate multiple putative drug treatments to arrest OF is well documented.2 Current treatment standards for SIRS/MODS/OF are generic, including fluid resuscitation, inotropes, mechanical ventilation, and kidney replacement therapy. While optimizing physiology is a worthy goal,3 there is an urgent need for a new paradigm to introduce effective treatment strategies that go beyond organ support to target specific disease mechanisms to mitigate SIRS/MODS/OF and the risk of death.