As a major cardiovascular risk factor for stroke, coronary artery disease, heart failure and end-stage renal disease, hypertension affects approximately one billion people and causes large economic burden worldwide. Cytochrome P450 3A5 (CYP3A5), belonging to the CYP3A subfamily, has been implicated in the regulation of blood pressure and may serve as a potential risk factor for the development of hypertension. Increased CYP3A5 activity could cause sodium and water retention by affecting the metabolism of cortisol in the kidneys. Furthermore, polymorphic CYP3A5 genotypes have been shown to cause differences in blood pressure response to antihypertensive drugs. Several studies have investigated the role of CYP3A5 in blood pressure response to amlodipine. However, recent data on the role of CYP3A5 in hypertension development and treatment are inconsistent. This review summarizes what is known regarding the relationship of CYP3A5 with hypertension, discusses the limitations in present studies, highlights the gaps and directs research to this field.