Importance of the field: Hypertension is the most common preventable cause of cardiovascular morbidity and mortality. Despite the availability of a multitude of antihypertensive drugs, blood pressure (BP) control rates remain poor in the majority of patients with hypertension due to both patient- and clinician-related factors. The purpose of this review is to describe how healthcare professionals can best utilize combination therapy to optimize patient antihypertensive treatment and achieve BP goals.Areas covered in this review: Data are discussed describing the common need for multiple antihypertensive agents for achieving BP control, importance of the time required for BP control on patient outcomes, and key clinical trial experiences for guiding decisions in antihypertensive regimen selection, with particular attention to the efficacy and tolerability of triple-therapy combinations and the benefits and disadvantages of single-pill formulations for combination regimens. Literature searches of these various topics were conducted in July 2009 (using no time period limits), with the paper later updated with published literature available as of May 2010 (including abstracts from the 2010 annual meeting of the American Society of Hypertension).What the reader will gain: The reader will derive an appreciation for general need for the use of two, and often three or more, antihypertensive agents for achieving BP goals, supporting the importance of thorough patient assessment in determining the appropriateness of combination therapy early in the course of treatment. They will also be updated as to the clinical trial data available for triple-therapy combinations, including both published and recently presented data.Take home message: By optimizing efficacy, decreasing side effects, and increasing adherence, combination therapy using single-pill combinations can improve outcomes in patients with mild to moderate hypertension.