With the implementation of new intensive care unit (ICU) therapies in the 1970s, multiple organ failure (MOF) emerged as a fulminant inflammatory phenotype leading to early ICU death. Over the ensuing decades, with fundamental advances in care, this syndrome has evolved into a lingering phenotype of chronic critical illness (CCI) leading to indolent late post-hospital discharge death. In 2012, the University of Florida (UF) Sepsis Critical Illness Research Center (SCIRC) coined the term Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) to provide a mechanistic framework to study CCI in surgical patients. This was followed by a decade of research into PICS-CCI in surgical ICU patients in order to define the epidemiology, dysregulated immunity, and long-term outcomes after sepsis. Other focused studies were performed in trauma ICU patients and emergency department sepsis patients. Early deaths were surprisingly low (4%); 63% experienced rapid recovery. Unfortunately, 33% progressed to CCI, of which 79% had a poor post-discharge disposition and 41% were dead within one year. These patients had biomarker evidence of PICS, and these biomarkers enhanced clinical prediction models for dismal one-year outcomes. Emergency myelopoiesis appears to play a central role in the observed persistent immune dysregulation that characterizes PICS-CCI. Older patients were especially vulnerable. Disturbingly, over half of the older CCI patients were dead within one year and older CCI survivors remained severely disabled. Although CCI is less frequent (20%) after major trauma, PICS appears to be a valid concept. This review will specifically detail the epidemiology of CCI, PICS biomarkers, effect of site of infection, acute kidney injury, effect on older patients, dysfunctional high-density lipoproteins, sarcopenia/cachexia, emergency myelopoiesis, dysregulated erythropoiesis, and potential therapeutic interventions.