The quest to eliminate the needle from insulin delivery and to replace it with non- or less-invasive alternative routes has driven rigorous pharmaceutical research to replace the injectable forms of insulin. Recently, various approaches have been studied involving many strategies using various technologies that have shown success in delivering insulin, which are designed to overcome the inherent barriers for insulin uptake across the gastrointestinal tract, mucosal membranes and skin. This review examines some of the many attempts made to develop alternative, more convenient routes for insulin delivery to avoid existing long-term dependence on multiple subcutaneous injections and to improve the pharmacodynamic properties of insulin. In addition, this article concentrates on the successes in this new millennium in developing potential non-invasive technologies and devices, and on major new milestones in modern insulin delivery for the effective treatment of diabetes.