In recent years major progress has been made in understanding the role of transcription factors in the development of the endocrine pancreas in the mouse. Here we describe how a number of these transcription factors play a role in maintaining the differentiated phenotype of the β cell, and in the mechanisms that allow the β cell to adapt to changing metabolic demands that occur throughout life. Amongst these factors, Pdx1 plays a critical role in defining the region of the primitive gut that will form the pancreas, Ngn3 expression drives cells towards an endocrine lineage, and a number of additional proteins including Pdx1, in a second wave of expression, Pax4, NeuroD1/β2, and MafA act as β cell differentiation factors. In the mature β cell Pdx1, MafA, β2, and Nkx2.2 play important roles in regulating expression of insulin and to some extent other genes responsible for maintaining β cell function. We emphasise here that data from gene expression studies in rodents seldom map on to the known structure of the corresponding human promoters. In the adult the β cell is particularly susceptible to autoimmune-mediated attack and to the toxic metabolic milieu associated with over-eating, and utilises a number of these transcription factors in its defence. Pdx1 has anti-apoptotic and proliferative activities that help facilitate the maintenance of β cell mass, while Ngn3 may be involved in the recruitment of progenitor cells, and Pax4 (and possibly HNF1α and Hnf4α) in the proliferation of β cells in the adult pancreas. Other transcription factors with a more widespread pattern of expression that play a role in β cell survival or proliferation include Foxo1, CREB family members, NFAT, FoxM1, Snail and Asc-2.