Glucagon-like peptide-2 (GLP-2) is a pleiotropic hormone that affects multiple facets of intestinal physiology, including growth, barrier function, digestion, absorption, motility and blood flow. This mechanisms through which GLP-2 produces these actions are complex, involving unique signaling mechanisms and multiple indirect mediators. As clinical trials have begun for the use of GLP-2 in a variety of intestinal disorders, the elucidation of such mechanisms is vital. The GLP-2 receptor (GLP-2R) is a G protein-coupled receptor, signaling through multiple G proteins to affect the cAMP and mitogen- activated protein kinase pathways, leading to both proliferative and anti-apoptotic cellular responses. The GLP-2R also demonstrates unique mechanisms for receptor trafficking. Expression of the GLP-2R in discrete sets of intestinal cells, including endocrine cells, subepithelial myofibroblasts and enteric neurons, has led to the hypothesis that GLP-2 acts indirectly through multiple mediators to produce its biological effects. Indeed, several studies have now provided important mechanistic data, illustrating several of the indirect pathways of GLP-2 action. Thus, insulin-like growth factor-1 has been demonstrated to be required for GLP-2-induced crypt cell proliferation, likely involving activation of -catenin signaling. Furthermore, vasoactive intestinal polypeptide modulates the actions of GLP-2 in models of intestinal inflammation, while keratinocyte growth factor is required for GLP-2-induced colonic mucosal growth and mucin expression. Finally, enteric neural GLP-2R signaling affects intestinal blood flow through a nitric oxide-dependent mechanism. Determining how GLP-2 produces its full range of biological effects, which mediators are involved and how these mediators interact is a continuing area of active research.