With the advent of dipeptidyl peptidase (DPP)-4 inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) over the past decade, incretin therapy has become established as an important treatment strategy for type 2 diabetes mellitus (T2DM), with an efficacy and safety profile distinct from that of other anti-hyperglycemic agents. However, our understanding of the optimal clinical use of incretins remains incomplete. This review focuses on the use of GLP-1 RAs in the treatment of T2DM, with reference to the differing dominant mechanisms of action between short- and long-acting GLP-1 RAs and the clinical implications of this difference. The role of GLP-1 and the effects of GLP-1 RAs in various organs other than the pancreas will also be discussed.