Streptozotocin (SZ) given in five low doses causes diabetes and an associated lymphocytic infiltration of the pancreatic islets. Using C57BL/KsJ-mice, we demonstrate a reduction in islet number (−38%) and volume (−64%) within 1 day following the last injection of SZ. A substantial fall of insulin secretory capacity (−84%) in the in vitro perfused pancreas matches the reduction in islet cell volume. The parameters of decreased islet function seem to precede the peak of lymphocytic infiltration, occurring 3 days after the last dose of SZ. These functional changes are readily demonstrable before a rise in fasting blood glucose, but they seem to be reflected more readily by a rise in nonfasting blood glucose levels. With development of overt diabetes, as measured by elevated fasting and nonfasting glucose levels, the measures of islet volume and function are reduced to levels only 1–2% of those found in control mice. Taken together, these observations reflect a rapid, islet-toxic effect of SZ that substantially decreases insulin secretory capacity. When islet function falls more than 90%, blood glucose levels begin to reflect the pathophysiologic process. In many aspects, the low-dose SZ model of diabetes parallels the development of diabetes in man. If so, measures other than blood sugar must be developed to identify at an early stage processes reducing islet volume and function.