Apolipoprotein E (APOE) is a major protein component of peripheral and brain lipoprotein transport systems. APOE in peripheral circulation does not cross blood brain barrier or blood cerebrospinal fluid barrier. As a result, peripheral APOE expression does not affect brain APOE levels and vice versa. Numerous epidemiological studies suggest a key role of peripherally expressed APOE in the development and progression of coronary heart disease while brain APOE has been associated with dementia and Alzheimer's disease. More recent studies, mainly in experimental mice, suggested a link between Apoe and morbid obesity. According to the latest findings, expression of human apolipoprotein E3 (APOE3) isoform in the brain of mice is associated with a potent inhibition of visceral white adipose tissue (WAT) mitochondrial oxidative phosphorylation leading to significantly reduced substrate oxidation, increased fat accumulation and obesity. In contrast, hepatically expressed APOE3 is associated with a notable shift of substrate oxidation towards non-shivering thermogenesis in visceral WAT mitochondria, leading to resistance to obesity. These novel findings constitute a major paradigm shift from the widely accepted perception that APOE promotes obesity via receptor-mediated postprandial lipid delivery to WAT. Here, we provide a critical review of the latest facts on the role of APOE in morbid obesity.