Many questions about the natural history of both type 1 and type 2 diabetes remain unanswered, mostly because what we have experimentally learned has been derived from in vitro studies, which only partially mimic the complex situation of the living animal/human. Furthermore, the in vivo observations that can now be made in living individuals provide but indirect evaluations of beta cell mass and functions (in humans), or allow for testing only a single time point along the sequence of events that leads to the onset, maintenance and evolution of the diseases (in animal models). As a consequence, we lack a solid scientific basis to develop targeted therapies, and to monitor their actual effects, specifically in the human clinic. In view of the explosive diabetic epidemic, a method that could non invasively and repeatedly evaluate both beta cell mass and function, the two parameters whose alterations are key to most forms of diabetes, is now most needed.