Chlorthalidone's safety and efficacy in the management of hypertension has been demonstrated in landmark trials. Despite understanding the effects of thiazides on urinary sodium excretion and intravascular volume, the exact mechanism of their antihypertensive effects is not clearly understood. Common compensatory mechanisms for decreases in circulating plasma volume include increased adrenergic tone and systemic vascular resistance, as well as increases in the renin-angiotensin-aldosterone system. Chlorthalidone has been shown to decrease platelet aggregation and vascular permeability and promote angiogenesis in vitro, which is thought to be, in part, the result of reductions in carbonic anhydrase-dependent pathways, including catecholamine-mediated platelet aggregation and downregulation of VEGF-C gene expression. This article reviews the comparative clinical data between chlorthalidone and hydrochlorothiazide, the pharmacologic properties that might explain some of their differences regarding half-life and efficacy, and what is known about the effect of chlorthalidone on intermediate endpoints.