A grand challenge in the field of “smart” drug delivery has been the quest to create formulations that can sense glucose and respond by delivering an appropriate dose of insulin. This approach, referred to as the “fully synthetic pancreas”, envisions closed-loop insulin therapy. The strategies for incorporating glucose sensing into formulations can be broadly categorized into three subsets: enzymatic sensing, natural glucose-binding proteins and synthetic molecular recognition. Here, we highlight some examples of each of these approaches. The challenges remaining en route to the realization of closed-loop insulin therapy are substantial, and include improved response time, more authentic fidelity in glycemic control, improved biocompatibility for delivery materials and assurance of both safety and efficacy. The ubiquitous existence of glucose, combined with the unstable and toxic properties of insulin, further compound efforts towards the generation of a fully synthetic pancreas. However, given the growing incidence of both type-1 and type-2 diabetes, there is significant potential impact from the realization of such an approach on improving therapeutic management of the disease.