One of the main approaches to the treatment of cardiovascular diseases is to block pathways and enzymes within the Renin-Angiotensin System (RAS) involved in the modulation of Angiotensin II. Besides this complex system, many other alternative strategies may represent interesting targets for new and more effective cardiovascular therapies. Many different approaches have led medicinal chemists to develop new molecules with the aim of improving current antihypertensive therapies. The development of these new compounds is based on different strategies which include the synthesis of new hybrid compounds in which two or more pharmacophore groups are combined together to give a new entity with better pharmacodynamic properties and fewer side effects, and the development of new molecules with targets such as renin, angiotensin (1-7) and urotensin-II. The aim of this review is to present various approaches used to improve antihypertensive therapy, developing both original molecules with new mechanisms of action (such as renin inhibitors, or Mas-agonists) and new hybrid cardiovascular drugs targeting multiple factors involved in hypertensive disease (NO-ACE inhibitors, NO-sartans, AT1/ETA antagonists).