The endothelium has emerged as a crucial component of the innate immune system, a central regulator of the inflammatory response, and a driver of organ damage. There is an urgent clinical need to better understand how to prevent and treat severe systemic inflammatory reactions. Here, the mechanisms driving cytokine-mediated endotheliopathy are discussed, with a special emphasis on the signaling downstream of interleukin 6 and its potential role during critical illness, including septic shock and severe COVID-19. Our understanding obtained from animal models of disease is complemented with the limited knowledge obtained from clinical biospecimens. Important gaps in our knowledge are described in the context of potential therapeutics and patient stratification.