A large proportion of patients with hypertension require a second blood pressure-lowering drug to reach blood pressure control. None of the major clinical trials of blood pressure drugs have compared, in a random fashion, the efficacy of the second drug in the prevention of hard outcomes and only one large observational study has evaluated the link between different associations of drugs and the incidence of cardiovascular disease. There are a few well-designed clinical trials comparing the blood pressure-lowering effect of drugs added with the first option. Therefore, choosing the second option is largely empirical and still not based on the best standards of evidence-based medicine, resulting in vague recommendations from guidelines. A large NIH-sponsored trial comparing the second choice in patients already on diuretics has been planned. For now, in the absence of a sound basis for choosing the second blood pressure-lowering agent, the classical stepped-care approach recommended by the first National High Blood Pressure Education Program may still be a valid guideline.