Pancreas plays an important role in maintaining the glucose homeostasis. The deterioration of β-cells in the pancreas is a crucial factor in the progression of diabetes mellitus; therefore, the restoration of β-cell mass and its function is of vital importance for effective therapeutic strategies. The precise mechanism for increase in functional β-cell mass is still unknown. This review focuses on the importance of certain genes which are involved in the rejuvenation of pancreas. These genes are divided according to their functions into three categories: participate either in proliferation (mitotic division of differentiated β-cells), neogenesis/transdifferentiation (development from precursor cells) or inhibition of β-cell apoptosis (programmed cell death). The rate of β-cell rejuvenation is the balance among the rates of β-cell proliferation, neogenesis and apoptosis. Understanding these genes and their pathways may lead to the discovery of new drugs, target based gene delivery and development of safer antidiabetic drugs.