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Since the introduction of chlorothiazide into clinical practice in 1958, thiazide-type diuretics have weathered decades of criticism and controversy. Fifty years later, they remain the single most important class of antihypertensives available. Numerous clinical trials across broad populations consistently demonstrate superior reductions in cardiovascular outcomes with thiazide-based regimens and most notably using the thiazide-like diuretic, chlorthalidone. Recent evidence suggests there may be important differences among thiazides that favor chlorthalidone due to its longer half-life and duration of action. Despite their proven record, thiazide diuretics continue to be scrutinized for their well-known adverse metabolic profile, especially hypokalemia. Glucose intolerance and incident diabetes with diuretic therapy has received significant attention; however, evidence from the ALLHAT study and others indicate the reductions in cardiovascular outcomes with thiazides are also observed in diabetics. Potassium depletion may be associated with diuretic dysglycemia. To minimize the adverse metabolic profile of thiazides, clinicians should preferentially use low doses. Combinations with potassium-sparing agents, or with renin-angiotensin system drugs such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers should also be considered. The last fifty years has seen remarkable advances in our understanding and treatment of hypertension and thiazides remain the most important pharmacologic advancement in our therapy of hypertension.