The diabetes pipeline has thrown up a range of candidate pharmaceuticals in the last 10 years. Starting with the disappointments, recent studies have raised serious questions concerning two groups of drugs which lower blood glucose concentrations in type 2 diabetes. First, the adverse effect profile (especially nephrotoxicity) of the potent peroxisome proliferator-activated receptor (PPAR) α and PPAR γ agonist aleglitazar may mean the end of PPAR modulation as a therapeutic modality, especially since a variety of other drugs in this class have previously been withdrawn. The promising G-protein-coupled receptor (GPCR) 40 agonist class has also come under a cloud since fasiglifam, the lead compound, was withdrawn during Phase 3 evaluation because of liver toxicity. Other agents in the pipeline include the 11β-hydroxysteroid dehydrogenase inhibitors, glucokinase activators (although hepatic triglyceride accumulation and time-restricted blood glucose lowering effect are disadvantages), glucagon receptor antagonists, immunomodulatory drugs (such as salicylates and anakinra), and the peptide oxyntomodulin (which has glucagon/GLP-1 dual agonist activity).