Alternative treatments for diabetes are currently being investigated to improve both patient comfort and avoid complications due to hyperglycaemia episodes. In the absence of a cure like pancreas or beta-islets transplants, the ideal method would be an artificial "closed-loop" system able to mimic pancreas activity. This would operate continuously and automatically, causing appropriate response to losses and gains in glucose levels. Chemically controlled closed-loop insulin delivery has been explored by two main strategies. The first one consists in delivering insulin with a glucose-responsive matrix. Polymeric hydrogels that swell or shrink according to the glucose concentration allow delivering insulin doses adapted to the glucose concentration. The second strategy consists in modifying insulin itself with glucose-sensitive functional groups that trigger its activity. Recent developments made in these areas represent significant progress in terms of biocompatibility, selectivity, pharmacokinetics, and easiness of administration, as required for in vivo applications. Although some issues still have to be overcome, this field of research is promising as a possible alternative to other approaches for diabetes treatment.