The increasing incidence of diabetes requires a better understanding of the pathogenesis of the clinical disease. Studies in prevention and treatment have been hampered by the single end-point of diagnosis of diabetes and hyperglycemia. The common pathology in both type 1 and type 2 diabetes is insufficient beta-cell mass to meet the metabolic demand. Unfortunately, current diagnostic methods rely on metabolic responses that do not accurately reflect true beta-cell mass. Recent advances in beta-cell imaging have utilized multiple modalities in experimental and clinical settings. While no gold-standard exists to measure beta-cell mass, modalities such as single photon emission computed tomography, optical and fluorescent imaging, magnetic resonance imaging, and positron emission tomography have been used with mixed success. Many of the methods are limited by the inability to translate to the clinical setting, poor discrimination between the exocrine and endocrine pancreas, or a poor measurement of beta-cell mass. However, promising new neurofunctional imaging approaches have emerged as improved measures of beta-cell mass. We review the current understanding of the pathogenesis and evaluation of diabetes, as well as experimental approaches to assessing beta-cell mass.