The state of the endothelium defines vascular health–ensuring homeostasis when intact and driving pathology when dysfunctional. The endothelial cells (ECs) which comprise the endothelium are necessarily highly responsive and reflect their local mechanical, biological, and cellular context, making a concrete definition of endothelial state elusive. Heterogeneity is the hallmark of ECs and has long been studied in the context of structural and functional differences between organs and vascular beds. More recently, local heterogeneity within vessels has also been demonstrated. Understanding the impact of local heterogeneity on EC function in health and disease requires complete description of the heterogeneous states occupied by ECs under physiologic conditions and methods for defining the components of and variability in plasticity in EC state in response to disease-relevant stimuli. Recent technological advances in transcriptional characterization with single-cell resolution including single-cell RNA-sequencing (scRNA-seq) enable high-resolution study of the EC response to a range of stimuli.