The first idea  for a glucose-responsive insulin (GRI, commonly referred to as smart insulin) was pitched almost 40 years ago, but to our knowledge only one compound has since undergone clinical evaluation. It seems a little surprising that it takes such a long time to develop a functioning GRI because its concept is actually relatively simple: At normal glucose concentrations, small amounts of insulin are released to keep blood glucose (BG) fairly constant. In response to rising glucose concentrations, for example after a meal, more insulin is released to limit the glucose rise and to return glucose concentrations back to normal. This closed-loop insulin release should limit BG variability and because insulin is only released when it is needed, it should also reduce the risk of over- and underdosing insulin. Two key elements are needed for a GRI: (1) A component that can ‘sense’ glucose and (2) a component that can respond and control the release of insulin. The concept may be simple, suggested solutions are complex and diverse .