The common forms of abnormal glucose regulation including type 2 diabetes and impaired glucose tolerance with pathological implications on vascular biology have a complex aetiology involving multiple cross-talks between genetic influences and important environmental modifying factors. Due to complexity of the genetics and the clinical heterogeneity of these disorders it has proven difficult to apply the same methodological approaches that have recently given insights into the molecular genetics of several single-gene disorders of glucose metabolism. This review gives some reflections on the challenges posed by the current hypotheses about the genetics of the widespread forms of abnormal glucose regulation as well as on the strengths and limitations of the methodological approaches applied to unravel the genetic components of common disorders. Also, we review recent progress in relation to a model for the pathogenesis of the various stages of abnormal glucose regulation based on the concepts of thrifty genes of metabolism and pro-inflammation and genes responsible for the appearance of impaired pancreatic beta-cell function and insulin signalling under the pressure of a westernized environment.