This is an overview of recent findings, mainly from our laboratory, describing the cardiovascular functional phenotypes and pharmacological responses in mice genetically deficient in apolipoprotein E (apoE-KO). ApoE-KO mice are hyperlipidemic and spontaneously develop atherosclerosis. We have detected several new cardiovascular functional phenotypes in apoE-KO mice: hyperglycemia, age-dependent aortic stiffening, cardiac hypertrophy and increased cardiac output. Angiotensin II (Ang II) promoted vascular inflammation and atherosclerosis, increased vascular stiffness, and induced abdominal aortic aneurysm (AAA) in apoE-KO mice, in which activation of NF-kappaB mediated pro-inflammatory genes plays an important role. Inhibition of nitric oxide (NO) synthesis with N(omega)-nitro-L-arginine methyl ester (L-NAME) significantly inhibited NO-mediated vascular responses and accelerated atherosclerosis in apoE-KO mice, supporting a protective role of NO against atherosclerosis. Estrogen attenuated atherosclerosis in apoE-KO mice, even in those with atherosclerosis being accelerated by Ang II, hyperglycemia, or L-NAME, demonstrating an anti-atherosclerotic effect of estrogen. Simvastatin paradoxically increased lipid and atherosclerosis in apoE-KO mice, but it decreased lipid and atherosclerosis in LDLR-KO mice, indicating that anti-atherosclerotic effect of simvastatin requires the presence of an intact apoE.