The plant-derived triterpenoids, commonly used in many Asian countries, display several important pharmacological properties. Starting from pentacyclic oleanane triterpenoids, synthetic triterpenoids have been synthesized, resulting in the production of potent compounds that display a marked suppressive effect on oxidative and inflammatory stress and pronounced cytoprotective effects. All these important pharmacological properties have triggered the investigation of these molecules in a wide spectrum of preclinical disease models. Here, we review the rationale for the use of natural and synthetic triterpenoids as protective agents for cardio-vascular system. Experimental studies have shown that triterpenoids exert an anti-atherogenic effect, and protect against cardiac ischemia through various mechanisms, particularly through NRF2 activation, with consequent induction of anti-oxidative genes and stimulation of nitric oxide (NO) production, inducing vasodilatation and vasorelaxation. Given these pharmacological properties, a synthetic triterpenoid, derivative of oleanane, CDDO-ME (Bardoxolone Methyl) was introduced in clinical studies. At low nanomolar concentrations CDDO-ME protects the cells against oxidative stress through the inhibition of reactive oxygen species (ROS) production, whereas at higher concentrations it triggers apoptosis via induction of ROS production and decrease of reduced intracellular glutathione levels. As a multifunctional agent, CDDO-ME can be used as a drug that protect against excessive pathological oxidative stress and inflammation and as an anti-tumor drug. Furthermore, tanshinone IIA, a triterpene extracted from the dried root of Salvia miltiorrhizae, is under clinical investigation for its anti-atherogenic and cardioprotective effects.