Hypoglycemia, the condition of low blood sugar, is a common occurance in people with diabetes using insulin therapy. Protecting against hypoglycaemia by engineering an insulin preparation that can auto-adjust its biological activity to fluctuating blood glucose levels has been pursued since the 1970s, but despite numerous publications, no system that works well enough for practical use has reached clinical practise. This review will summarise and scrutinise known approaches for producing glucose-sensitive insulin therapies. Notably, systems described in patent applications will be extensively covered, which has not been the case for earlier reviews of this area. The vast majority of published systems are not suitable for product development, but a few glucose-sensitive insulin concepts have recently reached clinical trials, and there is hope that glucose-sensitive insulin will become available to people with diabetes in the near future.