This overview considers the opportunities and challenges that face the use of gluco-regulatory peptides to treat type 2 diabetes. New insulin analogues and formulations are being developed with pharmacokinetic properties to speed-up or prolong transfer from a subcutaneous injection site to the target tissues, or to selectively favour effects on the liver. Alternative routes of insulin administration continue to attract attention, and advances in the integration of glucose monitoring with insulin pump devices are improving miniaturised ‘closed loop’ artificial pancreas systems. Proof of concept has been established for non-cellular glucose-responsive insulin delivery (‘smart insulins’) to release insulin from implants or circulating depots in proportion to circulating glucose. The many peptides involved in blood glucose control offer diverse therapeutic opportunities. Exploitation of multiple selected receptor targets using constructs of hybrid and chimeric peptides, especially those based on glucagon and gastrointestinal hormones, has gained much credence from initial preclinical studies. Peptide templates identified from comparative endocrine studies have also provided valuable insights in this respect and indicated novel approaches to address associated conditions such as obesity and infections at the same time. Nevertheless, there are many challenges to the use of therapeutic peptides that impose on every step in the complex pathway from design and testing through to making a fully characterised therapeutic product, and optimising administration, tissue targeting and degradation. Stability of peptides and immunological uncertainties of novel structures require particular consideration as well as the need to avoid over-reduction of blood glucose into hypoglycaemia.