It has long been known that antihypertensive drugs may affect blood glucose in a differential manner. In particular new onset diabetes is significantly increased in association with the use of thiazides or beta-blockers, respectively, compared to placebo, whereas treatment with angiotensin-conversion-enzyme-inhibitors or angiotensin-receptor-blockers is associated with a lower than expected frequency, as also assessed in several meta-analyses. In line with these notions, the NAVIGATOR Trial was the first to report a significant preventive effect of an angiotensin-receptor-blocker on new onset diabetes evaluated as a primary outcome in a prospective randomized study. Hence, and in view of the fact that comparable blood pressure lowering with any of the five major classes of antihypertensive drugs, including calcium-channel-blockers, give comparable benefits in reducing cardiovascular complications, unless there are specific indications or contraindications for an individual drug, caution should be exercised, therefore, to use beta-blockers or thiazides as first-line drugs for blood pressure lowering indications in subjects at high risk to develop diabetes, especially in patients with so called metabolic syndrome. The potential of glycemic worsening in overt diabetic patients with thiazides or beta-blockers has less well been studied systematically, yet paradigmatically in UKPDS evaluating a randomized comparison of a beta-blocker with an angiotensin-conversion-enzyme(ACE)-inhibitor. Not only was there HbA1c worsening with beta-blocker use which required additional blood glucose lowering therapy, but also significantly more weight gain which still was detectable at the 20 year follow-up. On the other hand, the overall cardiovascular outcomes were comparable in the two treatment groups irrespective whether therapy was based on the beta blocker atenolol or the ACE-inhibitor captopril. Awareness of these facts and highly individualized therapy seem to be the way forward.