Cardiovascular diseases constitute the largest of death in the Western world. Various stressors, including elevated blood pressure, smoking, diabetes, and hypercholesterolemia directly or indirectly damage the vessel wall, eventually inducing arterial stiffness (arteriosclerosis) and lipid accumulation (atherosclerosis). However, the molecular mechanisms of atheroma formation are not yet fully clarified. While many investigators have used proteomic techniques to study cardiac diseases, vascular proteomics is still in its infancy. The present review highlights studies, in which proteomics has been successfully applied to study protein alterations in the vasculature. Furthermore, we will summarize our recent progress in combining proteomic and metabolomic techniques to reveal protein and metabolite alterations in the cardiovascular system: two-dimensional (2-D) gel electrophoresis proved to be highly complementary to nuclear magnetic resonance (NMR) spectroscopy, in that post-translational modifications of the most abundant enzymes were displayed on 2-D gels while NMR spectroscopy revealed changes in the corresponding metabolites. Importantly, the simultaneous assessment of protein and metabolite changes translated purely descriptive proteomic and metabolomic profiles into a functional context and provided important insights into pathophysiological mechanisms that would not have been obtained by other techniques.