The glucagon-like peptide-1 receptor (GLP-1R) is a class B G-protein coupled receptor (GPCR) that has proven to be an effective target for developing medicines that treat type 2 diabetes mellitus (T2DM). GLP-1R agonists improve T2DM by enhancing glucose-stimulated insulin secretion, delaying gastric transit, decreasing glucagon levels, and reducing body weight due to anorexigenic actions. The therapeutic successes of these agents helped inspire the design of new multifunctional molecules that are GLP-1R agonists but also activate receptors linked to pathways that enhance insulin sensitization and/or energy expenditure. Herein, these agents are discussed in the context of polypharmacological approaches that may enable even further improvement in treatment outcomes. Moreover, we revisit classical polypharmaceutical GPCR approaches and how they may be utilized for treatment of T2DM. To determine optimal combination regimens, changes in drug discovery practices are likely needed because compensatory mechanisms appear to underlie progression of T2DM and limit the ability of current therapies to induce disease regression or remission.