The incidence of obesity and type 2 diabetes continues to rise across the globe necessitating the need to identify new therapeutic approaches to manage these diseases. In this review, we explore the potential for therapeutic interventions focussed on the intestinal epithelium, by targeting the role of this tissue in lipid uptake, lipid-mediated cross talk and lipid oxidation. We focus initially on ongoing strategies to manage obesity by targeting the essential role of the intestinal epithelium in lipid uptake, and in mediating tissue cross talk to regulate food intake. Subsequently, we explore a previously underestimated capacity of intestinal epithelial cells to oxidize fatty acids. In this context, we describe recent findings which have unveiled a key role for the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors and histone deacetylases (HDACs) in the regulation of lipid oxidation genes in enterocytes and how targeted genetic manipulation of these factors in enterocytes reduces weight gain, identifying intestinal PPARs and HDACs as potential therapeutic targets in the management of obesity.