The microvasculature is a heterogeneous, dynamic and versatile component of the systemic circulation, with a unique ability to locally self-regulate and to respond to organ demand and environmental stimuli. Endothelial cells from different organs display considerable variation but it is currently unclear to what extent functional properties of organ-specific endothelial cells are intrinsic, acquired and/or reprogrammable. Vascular function is a fundamental pillar of homeostasis, and dysfunction results in systemic consequences for the organism. Additionally, vascular failure can occur downstream of organ disease or environmental stress, often driving an exacerbation of symptoms and pathologies originally independent of the local circulation. The understanding of the molecular mechanisms underlying endothelial physiology and metabolism holds the promise to inform and improve diagnosis, prognosis and treatment options for a myriad of conditions as unrelated as cancer, neurodegeneration or pulmonary hypertension, and likely everything in between, if we consider that also treatments for such conditions are primarily distributed via the blood stream. However, studying endothelial function has its challenges: the origin, isolation, culture conditions and pre-conditioning stimuli make this an extremely variable cell type to study, and difficult to source. Animal models exist but are neither trivial to generate nor necessarily adequately translatable to human disease. In this article, we aim to illustrate the breath of microvascular functions in different environments, highlighting current and pioneering studies that have advanced our insight into the importance of the integrity of this tissue, as well as the limitations posed by its heterogeneity and plasticity.