To unravel the cellular and molecular mechanisms involved in beta-cell renewal and expansion throughout life, several different experimental models were devised in the past. A number of experimental approaches and transgenic models have been engineered to trigger specifically pancreatic injury and thus explore regeneration. Globally, three main strategies are followed to induce pancreas damage: surgical, chemical and genetic. Some of the most relevant studies regarding these three approaches are briefly summarized in this short overview. Although significant progress has been achieved in recent years, there is much room for improving our understanding of many fundamental processes regulating beta-cell mass maintenance.