This Perspectives in Diabetes addresses the accuracy of metabolic testing as a measure of pancreatic islet β-cell mass in vivo in animals and in humans. The impetus for framing this question lies in the current intense interest in determining the fate of β-cell mass in transplanted islets, i.e., does it decrease, increase, or remain the same over time, as well as ascertaining whether drugs that enhance incretin levels, and consequently enhance glucose-induced insulin secretion, might also preserve β-cell mass. An important methodology recently making scientific strides in this arena is positron emission tomography (PET). The central question this Perspectives in Diabetes raises is whether it is likely that PET will provide significant advantages over the metabolic methods already in hand and routinely used to estimate β-cell mass. This article examines the fidelity with which published metabolic data correlate with independent measures of β-cell mass across multiple species. Correlation coefficients in the general range of r = 0.80 are routinely obtained and are robust for in vivo research. Whether PET can significantly improve on these correlations, given its inherent limitations in measurement sensitivity, remains to be seen. It is clear that investigators developing PET methodology to estimate β-cell mass should at the same time incorporate metabolic measures into their studies so that side-by-side comparisons of the accuracy of the two experimental approaches can be made.