The 2018 European and 2017 American guidelines recommend to start antihypertensive treatment with combinations of two or more drugs in most hypertensive patients, as a consequence of the suggested more ambitious blood pressure (BP) targets (systolic BP between 130 and 120 mmHg in most patients, diastolic BP between 80 and 70 mmHg). Monotherapy, however, is still suggested as first choice in some specific classes of patients. In this article, we analyze the subgroups of hypertensive patients that should properly started and even maintained on monotherapy, with a focus on subjects with BP in the high-normal range or grade 1 hypertension, young adults with estimated low cardiovascular risk, women during pregnancy or menopause, elderly patients aged >80 years or with frailty parameters. Altogether, these subgroups cover a relatively large proportion of patients with hypertension. Thus, we conclude that, despite the upgrowing role of combination therapy, there is still ample room for the approach with monotherapy in clinical management of hypertension.