In the last decade, C-reactive protein (CRP) has attracted much interest as an independent predictor of cardiovascular events. Coincident with this interest in CRP epidemiology our laboratory pursued studies of CRP biology, focusing on the possible involvement of human CRP in the vascular remodeling process in genetically engineered mice. There is still no direct evidence that CRP contributes to vascular disease in humans, but by combining transgenic mice expressing human CRP in a manner that parallels human expression, and appropriate vascular disease models, we have shown that human CRP is indeed integral to cardiovascular disease. For example, CRPtg mice experience much more rapid and higher rates of complete thrombotic occlusion after vascular injury than their wild type counterparts, and transgenically expressed human CRP exacerbates neointima formation after carotid artery ligation. The latter process is mediated by CRP binding to the FcγRI receptor on macrophages and henceforth initiating an inflammatory cascade. Indeed, pharmacological inhibition of human CRP expression in CRPtg (using estrogen or a human CRP targeting antisense inhibitor) not only lowers the serum level of CRP in CRPtg but also ameliorates the neointimal response to injury. In ApoE-/- mice we showed that expression of high amounts of human CRP worsened atherosclerosis, a process we now think involves endothelial dysfunction, possibly via reduced nitric oxide bioavailability. We are currently characterizing the phenotype of newly developed CRP "knock-out" mice: unique animals that do not express any CRP. Comparing vascular remodeling in CRP knockout mice to CRPtg (which express human CRP as an acute phase reactant) as well as to wildtype mice (which express low levels of mouse CRP at baseline but not as an acute phase reactant) will allow us to determine the effect of baseline or 'high sensitivity' CRP and acute phase CRP on this process. We and others have provided strong evidence that CRP is more than just a strong predictor of cardiovascular events, but that it is also intimately involved in the vascular response to injury. Clinical trials with CRP lowering drugs will be needed before it is known with confidence if interrupting CRP-mediated pathway in humans is beneficial in the treatment of cardiovascular disease, but the ability to perform those trials now exists. © 2009 by Nova Science Publishers, Inc. All rights reserved.