Plasma total homocysteine (Hcy) has been associated with cardiovascular risk in multiple large-scale epidemiological studies, and it has been considered as an independent risk factor for atherosclerosis. Homocysteine lowering, achieved after the introduction of the folate food fortification programme in North America, was accompanied by an accelerated decline of cardiovascular risk and especially of stroke. Although the initial clinical trials suggested that homocysteine-lowering treatment with folates and B vitamins induces coronary plaque regression, this finding was not confirmed by more recent clinical studies. Under the light of the findings from the recent large randomized clinical trials that failed to document a benefit of Hcy lowering on clinical outcome of patients with atherosclerosis, the role of Hcy as a risk factor and the efficacy of Hcy lowering against atherosclerosis have been questioned. Therefore, better understanding of the mechanisms relating Hcy and Hcy-lowering treatment with vascular function and atherogenesis is crucial, to help us understand why clinical trials failed to show a benefit from Hcy-lowering treatment. Are these therapeutic strategies ineffective because they fail to reduce intracellular Hcy levels and vascular redox state or should Hcy stop being considered as an independent risk factor for atherosclerosis from now on? In this review article, we provide a global approach of the molecular mechanisms relating Hcy with cardiovascular risk and introduce possible mechanistic explanations regarding the inability of clinical trials to detect any clinical benefit from Hcy-lowering treatment in secondary prevention. Finally, we provide clinical recommendations regarding the therapeutic strategies targeting homocysteine in the general population.