Insulin, a crucial polypeptide drug in management of diabetes, is degraded by the gastrointestinal enzymes and in the acidic harsh conditions of the stomach, following oral administration. Subcutaneous injection, although being effective, has several challenges and drawbacks. In the current study, the manuscript started by introduction about diabetes mellitus, its types, the complications of it on different body systems. Also, the manuscript discussed the role of insulin to regulate blood glucose concentration. The types of therapeutic insulin were discussed. Nanoparticle delivery systems used for delivery of insulin were mentioned in details such as liposomes, polymeric micelles, solid lipid nanoparticles and Nano-gels. Finally, the different routes of insulin administration are addressed such as subcutaneous, oral, rectal, pulmonary, buccal and vaginal routes.