Reproducibly differential responses to different classes of antihypertensive agents are observed among hypertensive patients, and may be due to interindividual differences in hypertension pathology. Computational models provide a tool for investigating the impact of underlying disease mechanisms on the response to antihypertensive therapies with different mechanisms of action. Here we present the development, calibration, validation, and application of an extension of the Guyton/Karaaslan model of blood pressure regulation. The model incorporates a detailed submodel of the Renin Angiotensin Aldosterone System (RAAS), allowing therapies that target different parts of this pathway to be distinguished. Literature data on RAAS biomarker and blood pressure responses to different classes of therapies were used to refine the physiological actions of Angiotensin II and aldosterone on renin secretion, renal vascular resistance, and sodium reabsorption. The calibrated model was able to accurately reproduce the RAAS biomarker and blood pressure responses to combinations of dual-RAAS agents, as well as RAAS therapies in combination with diuretics or calcium channel blockers. The final model was used to explore the impact of underlying mechanisms of hypertension on blood pressure response to different classes of antihypertensive agents. Simulations indicate that the underlying etiology of hypertension can impact the magnitude of response to a given class of therapy, making a patient more sensitive to one class and less sensitive others. Given that hypertension is usually the result of multiple mechanisms, rather than a single factor, these findings yield insight into why combination therapy is often required in order to adequately control blood pressure.