European guidelines recommend that treating patients with hypertension to blood pressure (BP) goal is an important target for cardiovascular (CV) risk reduction. However, office BP may be a suboptimal target, given its limitations. Indeed, there is evidence that 24-h ambulatory BP monitoring (ABPM) parameters may score better in this regard, representing more accurate predictors of CV risk. In particular, mean 24-h BP and BP variability both correlate closely with hypertension end-organ damage and rate of CV events, which suggests that antihypertensive therapy should provide smooth BP control over the full 24-h dosing interval. The use of ABPM has demonstrated that fixed-dose combination therapy, comprising agents with complementary mechanisms of action, may overcome the challenge of suboptimal BP control by providing improvements in antihypertensive efficacy and tolerability throughout the 24-h period. Olmesartan/amlodipine is one of the latest combination therapies to be approved, and a number of large clinical trials have demonstrated the efficacy and tolerability of this combination in patients with mild-to-severe hypertension. Furthermore, recent ABPM studies of olmesartan/amlodipine-based treatment algorithms have shown the satisfactory 24-h antihypertensive efficacy of this fixed-dose combination. This review provides an overview of recent clinical data on the efficacy and tolerability of fixed-dose olmesartan/amlodipine combination therapy for the treatment of mild-to-severe hypertension, with a focus on sustained 24-h BP control.