Heart rate, systolic blood pressure and responses of spontaneously hypertensive rats (SHR) to guanethidine, timolol, minoxidil and phentolamine were monitored at 2, 6 and 12 months of age. All antihypertensive agents produced significant and comparable reductions in systolic blood pressure at 6 and 9 months of age, at which time systolic blood pressures were maximally elevated, but had very little effect at 2 months when pressures were only marginally higher. However, at 12 months of age, SHR maintained their response to guanethidine and timolol but responded less well to minoxidil and, especially, to phentolamine. Aortic strips of SHR contracted less than those of normotensive rats to both KC1 and norepinephrine at all ages and also relaxed less to nitroglycerin. SHR aortic strips appeared to specifically lose the ability to contract to norepinephrine at 12 months of age. It is suggested that a progression of change in responsiveness to antihypertensive agents exists for SHR. Furthermore, this progression will differ for agents with differing mechanisms of action and is probably a result of physical and/or biochemical factors which combine to alter the responsivity of SHR vascular smooth muscle.