Proinsulin, the precursor of insulin during physiological insulin production, has been demonstrated in the past to stimulate PAI-1 secretion and consecutively block fibrinolysis. Therefore, proinsulin is contributing as an independent factor to the increased cardiovascular risk of patients with type 2 diabetes. However, development of insulin resistance in the course of type 2 diabetes leads to increased insulin demands and finally to an impairment of beta-cell function in later disease stages. Appearance of intact proinsulin in the peripheral blood has been shown to be a good laboratory marker for this phenomenon since it indicates an exhaustion of the cleavage capacity of the intracellular processing enzymes. However, the close relation of the two pathophysiological entities also makes it a very specific marker for insulin resistance per se. During the past years, new immunoassays have been developed that are able to distinguish between intact proinsulin and its specific and unspecific cleavage products. Use of these assays in recent epidemiological and intervention studies has helped to get a better understanding about beta-cell dysfunction and its relation to insulin resistance and cardiovascular risk. In a large cross-sectional study with 4270 orally treated patients, elevation of fasting intact proinsulin was very closely related to insulin resistance, as assessed by iv glucose tolerance test in a subgroup, and by HOMA analysis in the entire patient population. Effective treatment of insulin resistance (e.g. with thiazolidindiones) led to a decrease in elevated proinsulin levels and to a decrease of the cardiovascular risk profile, while the levels remained high during sulfonylurea therapy. These results suggest to reconsider intact and total proinsulin as valuable diagnostic tools in diagnosis and treatment of type 2 diabetes. Based on the published data of the new specific immunoassays, patients with elevated intact proinsulin levels (> 10 pmol/L) should be regarded and treated as being insulin-resistant, while elevation of total proinsulin (>45 pmol/l) may help to identify the high cardiovascular risk patients. Both assays can thus be used to assess beta-cell function, to facilitate the selection of the most promising therapy, and may also serve to monitor treatment success in the further course of the disease.