Sepsis and septic shock are great challenges for the doctors who treat critically ill patients. A big part of the scientific community is performing researches about the pathophysiology and treatment of this clinical problem. The endothelium has a very significant role in the alterations that sepsis causes especially to the circulatory system. The disorders of the normal function of the endothelium include derangement of the vascular tone, increase of endothelium permeability, activation of the endothelial cells, production of various regulators and disorders of coagulation. Nitric oxide is the modulator that mediates the action of most vasodilators. The overproduction of nitric oxide during sepsis is possibly the most important cause of the vasopressor-resistant hypotension which characterizes septic shock. The levels of natriuretic peptides are also increased. These peptides act through several ways on the circulatory system both peripherally and directly on the myocardium. Endothelin, vasopressin, adrenomedullin and prostacyclin are vasoactive substances that have their own role in the regulation of the circulatory system during sepsis.