Hypertension is a major contributor to cardiovascular morbidity and mortality. However, blood pressure control in clinical practice still falls short of treatment recommendations. The reasons for this are manifold, and patient non-compliance with medication has been identified as one important factor. In this article, we discuss the various reasons for patient non-compliance and look at strategies to improve adherence, for example, simplifying the medication regimen and reducing side-effects in an asymptomatic disease such as hypertension. In this regard, combination treatment, and specifically fixed-dose combinations, have come a long way in enhancing tolerability, reducing counter-regulatory drug mechanisms and bringing blood pressure closer to target. We investigate the possibility of some combinations having clinical benefits beyond blood pressure control, as this may improve long-term cardiovascular outcomes. On the other hand, certain combinations may only have positive clinical outcomes in carefully selected patient groups, and are not recommended for the routine management of hypertension. Lastly, issues such as escape mechanisms in the renin-angiotensin-aldosterone system (RAAS) are discussed. These mechanisms play a role in treatment failure, and may require the use of new antihypertensive drug classes, such as direct renin inhibitors.