Therapy-resistant hypertension is a frequent finding in clinical practice. It is associated with a significantly increased risk for cardiovascular and renal events. Causes include but are not limited to erroneous blood pressure measurements, compliance issues, blood pressure increasing co-medication, and secondary hypertension. During the last years, several medical and interventional therapeutic approaches have been described and introduced into clinical practice. The goal of this paper is to summarize the clinically relevant diagnostic and therapeutic aspects related to therapy-resistant hypertension and to give an overview on the rational approach to this clinical problem.