Understanding the mechanisms regulating pancreatic beta cell mass is a major challenge in pancreas biology with direct clinical implications for future therapies to diabetes. Key questions in this field regard the regenerative potential of beta cells, the identity of the cell of origin for regenerating beta cells and the nature of signals that govern beta cell homeostasis. We have developed a transgenic mouse system for conditional ablation of beta cells, based on doxycycline-regulated expression of diphtheria toxin. The addition of doxycycline to the drinking water of transgenic mice leads to beta cell-specific death, disruption of islet architecture and the development of hyperglycemia. Doxycycline withdrawal often results in spontaneous normalization of blood glucose and the morphological signature of islet regeneration, exposing a surprising capacity of the pancreas to recover from a situation similar to type 1 diabetes. Preliminary evidence regarding the cellular origins of regenerating beta cells will be presented.