The aim to avoid underfeeding has resulted in relative overfeeding of patients in the early phase of critical illness, worsening instead of improving outcomes. Negative randomised controlled trials have triggered mechanistic studies to investigate possible mechanisms explaining harm, allowing more scientific interpretation of many unexpected results during the last decades. Whereas individualized evidence-based approach to nutrition is still only rarely available, discussing and understanding of pathophysiological mechanisms should assist in decision-making in clinical practice. Further exploration of mechanisms of harm and benefit, as well as development of new technologies are needed to better plan future nutrition studies.