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Type two diabetes (T2D) is a challenging metabolic disorder for which a cure has not yet been found. Its etiology is associated with several phenomena, including significant loss of insulin-producing, beta cell (β cell) mass via progressive programmed cell death and disrupted cellular autophagy. In diabetes, the etiology of β cell death and the role of mitochondria are complex and involve several layers of mechanisms. Understanding the dynamics of those mechanisms could permit researchers to develop an intervention for the progressive loss of β cells. Currently, diabetes research has shifted toward rejuvenation and plasticity technology and away from the simplified approach of hormonal compensation. Diabetes research is currently challenged by questions such as how to enhance cell survival, decrease apoptosis and replenish β cell mass in diabetic patients. In this review, we discuss evidence that β cell development and mass formation are guided by specific signaling systems, particularly hormones, transcription factors, and growth factors, all of which could be manipulated to enhance mass growth. There is also strong evidence that β cells are dynamically active cells, which, under specific conditions such as obesity, can increase in size and subsequently increase insulin secretion. In certain cases of aggressive or advanced forms of T2D, β cells become markedly impaired, and the only alternatives for maintaining glucose homeostasis are through partial or complete cell grafting (the Edmonton protocol). In these cases, the harvesting of an enriched population of viable β cells is required for transplantation. This task necessitates a deep understanding of the pharmacological agents that affect β cell survival, mass, and function. The aim of this review is to initiate discussion about the important signals in pancreatic β cell development and mass formation and to highlight the process by which cell death occurs in diabetes. This review also examines the attempts that have been made to recover or increase cell mass in diabetic patients by using various pharmacological agents.