Vascular disease remains a major cause of morbidity and mortality in diabetes mellitus, in spite of recent improvements in outcome, some of which may be modulated by improved endothelial function. Therapeutic strategies aimed directly at preventing, or minimising the extent of, these sequelae are required as an adjunct to treatments directed at normalising the metabolic milieu. The microvasculature, and the endothelium in particular, are early contributors to vascular dysfunction, thus raising the question as to how best to specifically target the endothelium. However, the expansive nature of the microvasculature, the varying demands that tissues have in terms of blood flow, and the heterogeneity that exists amongst cell types in different sites raises potential problems as to the practicality of such an approach. Further-more, temporal and genetic factors in the genesis of diabetic microvascular dysfunction may impact on therapeutic strategies. It is suggested that a systematic approach is required to understand the heterogeneity of the microvasculature, with particular emphasis on relating differences in gene and protein expression with functional properties. Such an approach may then provide the necessary information to allow exploitation of endothelial cell heterogeneity for unique targeted interventions, as well as providing the necessary rationale for pharmacological interventions (both prophylactic and corrective) aimed at the endothelium as a whole.