For more than 50 years following the discovery of thiazide and thiazide-like diuretics, these medications are still at the center stage of antihypertensive therapy. Thiazides are often crucial for aggressive management of hypertension in combination with other medications such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), but thiazide metabolic effects have long raised concern and their long-term clinical significance has been debated. This chapter contains a full discussion of the clinical relevance of thiazide metabolic effects (dysglycemia up to new-onset diabetes, hypokalemia, hyperuricemia, effects on serum lipid profile, steady activation of the renin-angiotensin-aldosterone system). Special attention is devoted to low-dose thiazide combinations with other antihypertensives. The overall risk–benefit ratio favors the large-scale adoption of such combinations. Some antihypertensive medications (eg, ARBs directly opposing thiazide-induced peroxisome proliferator activated receptor γ [PPARγ] downregulation with favorably modulating insulin release) may prove especially efficient and beneficial candidates for combined antihypertensive treatment with low-dose thiazides.