Diabetes is a disorder characterized by beta-cell loss or exhaustion and insulin deficiency. At present, knowledge is lacking on the underlying causes and for the therapeutic recovery of the beta-cell mass. A better understanding of diabetes pathogenesis could be obtained through exact monitoring of the fate of beta-cells under disease and therapy conditions. This could pave the way for a new era of intervention by islet replacement and regeneration regimens. Monitoring the beta-cell mass requires a reliable method for noninvasive in vivo imaging. Such a method is not available at present due to the lack of a beta-cell-specific contrast agent. The only existing method to monitor islet cells in vivo consists of labeling islet transplants with iron nanoparticles prior to transplantation and visualization of the transplanted islets by magnetic resonance imaging (MRI). Therefore, accurate assessment of the native beta-cell mass is still limited to autopsy studies. Endeavors to find a biological structure specific for beta-cells led to the discovery of potential candidates that have been tested for noninvasive imaging. Among them are the ligand to the vesicular monoamine transporter type 2 (VMAT-2), which is called dihydrotetrabenazine (DTBZ), antibodies to zinc transporter (ZnT-8) and the monoclonal antibody IC2. While DTBZ and antibodies to ZnT-8 showed binding activities to more than beta-cells, the anti-IC2 monoclonal antibody showed binding properties exclusively to insulin-producing beta-cells. This effect was demonstrated in many previous investigations, and has been further substantiated more recently. Thus, at present, IC2 seems to be the only useful marker for noninvasive functional imaging of native beta-cells. Experiments with a radioisotope-chelated IC2 structure on pancreas ex vivo showed that the tracer specifically bound to the beta-cell surface and could be detected by nuclear imaging. In the near future, these promising findings may offer a new way to monitor the beta-cell mass in vivo under disease and therapy conditions so that we can learn more about diabetes pathogenesis and options for disease prevention.