The changes in beta-cell mass (BCM) during the course of diabetes are not yet well characterized. A non-invasive method to measure the BCM in vivo would allow us to study the BCM during the onset and progression of the diseases caused by beta-cell dysfunction. PET and SPECT imaging are attractive approaches to determine the BCM because of their high sensitivity and the possibility to quantitatively analyze the images. Several targets and their corresponding radiotracers have been examined for their ability to determine the BCM including radiolabeled antibodies, antibody fragments, peptides and small molecules. Although some of these tracers show promising results, there is still no reliable method to determine the beta-cell mass in vivo. In this review, the targets and the corresponding radiotracers evaluated so far for the determination of the BCM in vivo in humans will be discussed.