Deficiency of alpha-galactosidase A (GLA) (Fabry disease) leads to the accumulation of glycosphingolipids in the vasculature leading to multiorgan pathology. In addition to well-described microvascular disease, deficiency of GLA is also characterized by premature macrovascular events such as stroke and possibly myocardial infarction. The mechanisms by which GLA may influence macrovascular disease are unclear. A mouse model of GLA deficiency has facilitated the study of glycosphingolipid metabolism abnormalities on macrovascular end points. This review addresses some of the potential pathways by which GLA deficiency may contribute to vascular complications.