Classical models of transcription in vascular endothelial cells, specifically the cis/trans paradigm, have limitations. For instance, how does the environment have chronic effects on gene expression in endothelial cells after weeks or years? When an endothelial cell divides, how is this information transmitted to daughter cells? Epigenetics refers to chromatin-based pathways important in the regulation of gene expression and includes three distinct, but highly interrelated, mechanisms: DNA methylation, histone density and posttranslational modifications, and RNA-based mechanisms. Together they offer a newer perspective on transcriptional control paradigms in vascular endothelial cells and provide a molecular basis for understanding how the environment impacts the genome to modify disease susceptibility. This alternative viewpoint for transcriptional regulation allows a reassessment of the cis/trans model and even helps explain some of its limitations. This review provides an introduction to epigenetic concepts for vascular biologists and uses topical examples in cell biology to provide insight into how cell types or even whole organisms, such as monozygotic human twins with the same DNA sequence, can exhibit heterogeneous patterns of gene expression, phenotype, or diseases prevalence. Using endothelial nitric oxide synthase (NOS3) as an example, we examine the growing body of evidence implicating epigenetic pathways in the control of vascular endothelial gene expression in health and disease.