A high serum cholesterol level is a risk factor for cardiovascular disease and has commonly been linked with worse outcomes. It is now well recognised that, in many critically ill patients, the opposite is true, with hypocholesterolaemia being associated with poor outcomes. In critical illness, particularly sepsis, total and high-density lipoprotein (HDL) cholesterol levels are commonly decreased, with varying changes in triglyceride levels. The magnitude of the changes seems to reflect the severity of inflammation. Plausible biological explanations exist to explain these associations, including an interaction of lipoproteins with endotoxin and the regulation of cytokine production. It remains unclear whether these observed alterations in lipid profile are a consequence of the physiological disturbance or whether they have a more causative role, worsening organ dysfunction or predisposing to infection. Lipid emulsions provide a vehicle for drug delivery, have become an important part of nutrition, and are emerging as a therapy for specific intoxications. The nature, dietary source and amount of lipid provided to critically ill patients may be enormously important and warrant more rigorous investigation. Further understanding of the alterations in lipid metabolism may have therapeutic implications in treatment of sepsis with specific compounds that manipulate lipid profiles, such as fibrates, statins, niacin and even reconstituted HDL.