Diabetes causes approximately 2.9 million deaths yearly, mainly through an increased risk of cardiovascular disease. In hypertensive diabetics, blood pressure reduction determines a significantly lower rate of cardiovascular and renal events. Conversely, reaching the generally recommended target of lower than 130/80 mmHg is a difficult challenge and, in most cases, two or more antihypertensive drugs are required. Until recently, there was a general consensus that combination treatment should include a diuretic as one of the two fundamental agents. However, recently published trials using calcium channel blockers plus renin-angiotensin system-blocking agents showed that such a combination reduces the risk of major cardiovascular events, provides greater renoprotection, and improves metabolic outcomes as compared with diuretic-based combinations. The present review explores the potential for an 'optimal' combination therapy in patients with diabetes mellitus and hypertension, in view of recent experimental and clinical evidence.