Raised levels of blood pressure result from the complex interplay of environmental and genetic factors. The complexity of blood pressure control mechanisms has major implications for individual responsiveness to antihypertensive drugs. The underlying haemodynamic disorder in the majority of cases is a rise in peripheral vascular resistance. This observation led to the discovery and development of increasingly sophisticated and targeted vasodilators, although many of the earlier antihypertensive drugs, by virtue of their actions blocking the sympathetic nervous system, had a vasodilator component to their mode of action. A recent meta-analysis of placebo controlled trials of monotherapy in unselected hypertensives, reports average (placebo-corrected) blood pressure responses to single agents of 9.1 mmHg systolic and 5.5 mmHg diastolic pressure. These average values disguise the extremely wide ranging responses in individuals across a fall of 20-30 mmHg systolic at one extreme, to no effect at all, or even a small rise in blood pressure at the other. The second factor determining individual responses to monotherapy is the extent to which initial falls in pressure are opposed by reflex responses in counter regulatory mechanisms that are activated following the blood pressure reduction. Thus, a satisfactory blood pressure response is rarely reached with monotherapy alone. What then is the next step if blood pressure is not a goal after the patient has been treated with monotherapy for a few weeks? Should you uptitrate, substitute or combine?