Critically ill children requiring treatment in a pediatric intensive care unit (PICU) suffer from anorexia and/or feeding intolerance. The resulting macronutrient deficit associates with poor outcome. Until recently, this association formed the basis for initiating enteral or parenteral feeding early to improve outcome. The multicenter "Early-versus-Late-Parenteral-Nutrition-in-the-Pediatric-Intensive-Care-Unit" randomized controlled trial (PEPaNIC-RCT) addressed whether this association is causal. It showed that early supplementation of insufficient/contraindicated enteral nutrition with parenteral nutrition, as compared with accepting a macronutrient deficit throughout the first week in the PICU, did not improve outcome. On the contrary, it caused more infections and prolonged organ support and PICU stay, and adversely affected neurodevelopmental outcomes 2 and 4 years later. Harm was present in all subgroups and appeared explained by the macronutrient dose, more specifically the amino-acid dose, not lipid or glucose doses. These findings corroborated results from large-scale adult RCTs. Mechanisms of harm from early enhanced nutrition comprised suppressed cellular repair pathways like autophagy and ketogenesis, suppressed illness-induced alterations in thyroid hormone metabolism, more iatrogenic hyperglycemia, increased urea cycle activity through anabolic resistance, and induction of epigenetic modifications that mediate longer-term developmental impairments. These results came unexpected to many pediatric intensivists. Hence, the paradigm has only slowly begun to shift toward more restrictive macronutrient administration in the acute phase of critical illness. Benefits of early fasting responses have become clear, provided micronutrients are given to prevent deficiencies and refeeding syndrome. These insights open perspectives for studies investigating novel nutritional strategies to activate fasting-induced cellular repair while avoiding prolonged starvation.