Most antihypertensive drugs act by counteracting vasoconstrictor mechanisms and lower blood pressure by lowering vascular resistance. The beta-blockers, which have the unique feature of counteracting cardiac sympathetic drive, seem to be a major exception to this generalization. Moreover, their degree of cardiodepression is not only directly correlated with the initial sympathetic tone, but also with their degree of intrinsic sympathicomimetic activity (ISA). Cardiodepression initially evokes a proportional rise in vascular resistance. As indicated by review of the literature, the antihypertensive effect of beta-blockers always parallels a decline in vascular resistance. Minimizing cardiac sympathetic drive by strict bedrest and studying beta-blockers with different degrees of ISA in 50 hypertensive patients showed that initially the effect of the drugs is offset by a rise in vascular resistance proportional to the fall in cardiac output. After that, blood pressure always fell parallel with the decline in vascular resistance. In the long run blood pressure and vascular resistance were always positively correlated, whatever the level of cardiac output. Thus, like all other antihypertensive agents, beta-blockers also lower blood pressure through interference with a vasoconstrictor mechanism.