In this chapter, we will analyse the mode of action and therapeutic use of the ‘direct-acting smooth muscle relaxant antihypertensor drugs’. We will include in this class of drugs those antihypertensive compounds which are supposed to relax vascular smooth muscle without interfering with identified cell receptors (adrenergic, dopaminergic, angiotensin II receptors, etc.). For historical reasons, hydralazine and its analogues will be presented in this chapter, but some recent experimental results suggest that these compounds may act at the neurovascular junction [1].