Now that the reduction in β-mass has been clearly established in humans with type 2 diabetes mellitus (T2DM) 1–4, the debate focuses on the possible mechanisms responsible for decreased β-cell number and impaired β-cell function and their multifactorial etiology. Appropriate inbred rodent models are essential tools for identification of genes and environmental factors that increase the risk of abnormal β-cell function and of T2DM. The information available in the Goto-Kakizaki (GK) rat, one of the best characterized animal models of spontaneous T2DM, are reviewed in such a perspective. We propose that the defective β-cell mass and function in the GK model reflect the complex interactions of three pathogenic players: (1) several independent loci containing genes causing impaired insulin secretion; (2) gestational metabolic impairment inducing a programming of endocrine pancreas (decreased β-cell neogenesis) which is transmitted to the next generation; and (3) secondary (acquired) loss of β-cell differentiation due to chronic exposure to hyperglycemia (glucotoxicity). An important message is that the ‘heritable’ determinants of T2DM are not simply dependant on genetic factors, but probably involve transgenerational epigenetic responses. Copyright © 2005 John Wiley & Sons, Ltd.