Fexaramine, a gut-restricted farnesoid X receptor (FXR) agonist, promotes glucose and lipid homeostasis, improves insulin sensitivity, promotes white adipose tissue browning, and stimulates nonshivering thermogenesis. Enhancement in energy expenditure due to an increase in amount of energy burned by brown and ‘beige’ adipocytes results in subsequent weight loss. Fexaramine is poorly absorbed into circulation when delivered orally, which limits systemic FXR activation and toxicity. An increase in β3-adrenoceptor signaling, activation of Takeda G protein-coupled receptor 5/glucagon-like peptide-1 (TGR5/GLP-1) signaling, and induction of fibroblast growth factor (FGF)-19/FGF-15 play crucial roles in fexaramine metabolic actions. Intestinal FXR activation is a promising, potentially safe approach for treating obesity and metabolic syndrome.