Non-responders are frequently encountered in clinical practice, and different strategies have to be considered as well as diagnostic approaches. Nearly 50% of all hypertensive patients will require more than one drug to control blood pressure. The complexity of high blood pressure is reflected in the different responses to antihypertensive agents with varied mode of action. White coat hypertension may coexist with sustained hypertension and complicate interpretations of blood pressure measurements. Noncompliance is a challenge for the doctor, and may be difficult to solve. It depends not only on the patient-doctor relationship, but also on the patient's perception of own health and the side effect profile of the drugs. Patient education is crucial. Secondary hypertension should be excluded in truly resistant hypertension. Volume overload is frequent in essential hypertension, and volume expansion follows an excessive dietary sodium intake. These and other possibilities should be sought for when explaining failure to respond to antihypertensive therapy.