The nuclear receptors, LXRs and FXR, are important regulators of lipid homeostasis. Among their identified target genes is Apo E, which is a well-established plasma lipid transport protein. This lipoprotein has been extensively studied and a wide range of excellent reviews is available on it. Here, we reviewed the current status of Apo E regulation by LXRs and FXR, although a handful of publications are available on this topic. Functional response elements for LXRs and FXR have been identified in the Apo E / C-I / C-IV / C-II gene cluster. The emerging picture is that FXR regulates Apo E expression in the liver, whereas LXRs play a similar role in extrahepatic tissues. We further investigated the regulation of Apo E expression through LXR and FXR activation in liver- (HepG2), monocyte- (THP-1) and colon- (Caco-2) derived cell lines. Apo E transcript levels are increased in these three cell lines in response to LXR activation by the specific agonist T0901317. Upon FXR stimulation by GW4064, Apo E mRNA levels are increased in HepG2 and Caco-2, but not in the THP-1 cells, which do not express FXR. Interestingly, in the liver-derived HepG2 and colon-derived Caco-2 cell lines, which both express LXRs and FXR, Apo E expression can be controlled either by LXRs or FXR. In summary, these nuclear receptors display both distinct and overlapping functions in lipid metabolism. Apo E can be regulated by either LXRs or FXR, thus providing alternative mechanisms that control lipid homeostasis in different tissues.