Sepsis is an acquired clinical syndrome, with symptoms resulting from a systemic host response to infection [1]. Sepsis is the most common cause of death among hospitalized patients in noncardiac intensive care units and has instigated much preclinical and clinical research [2]. Recently, tremendous progress has been made in understanding the complex triad of infection, infl ammation, and coagulation during sepsis. It is now well established that in sepsis systemic infl ammation leads to activation of the coagulation system and inhibition of anticoagulant mechanisms and fi brinolysis (see Fig. 1). Activation of coagulation and subsequent fi brin deposition may be essential parts of the host defense against infectious agents in an attempt to contain the invading microorganisms and the subsequent infl ammatory response [3]. However, an exaggerated response can lead to a situation in which coagulation itself contributes to disease, in its most severe form leading to microvascular thrombosis and consumption of coagulation factors, a syndrome known as disseminated intravascular coagulation (DIC) [4]. DIC is a common feature in sepsis, particularly in septic shock where the incidence is between 30 and 50%, and it plays an important role in the development of multiple organ failure (MOF) [5]. One of the important hallmarks of sepsis is microvascular dysfunction in which endothelial activation and dysfunction play a pivotal role [6]. In infection and subsequent sepsis, components of the bacterial cell wall as well as host-derived mediators activate pattern recognition receptors on the endothelial surface [7, 8]. The endothelium responds to this with structural and, importantly, functional changes, such as increased vascular permeability. This results in redistribution of body fl uid and edema, which contribute to hypovolemia and hypotension that are important signs of the sepsis syndrome [6]. In normal situations the endothelium functions as an antithrombotic surface, preventing inappropriate activation of coagulation on the cell membrane [9]. However, when in sepsis the endothelium becomes activated, it transforms into a prothrombotic interface that is critically involved in the detrimental cascade leading to DIC and MOF (see Fig. 1). It is becoming increasingly clear that infl ammation not only leads to activation of the coagulation system, but that, vice versa, components of the coagulation system are also able to markedly modulate the infl ammatory response [10]. Tissue factor (TF), thrombin, the protein C (PC) pathway, activators and inhibitors of fi brinolysis, and protease-activated receptors (PARs) have all been shown to play vital roles in the crosstalk between coagulation and infl ammation in sepsis. In recent years, research in the fi eld of coagulation and infl ammation in sepsis has expanded its focus, now also covering, for example, microparticles (MPs) and platelets. In this chapter, the key players in inflammation-induced coagulation and coagulation-induced inflammation in sepsis are discussed with a special focus on the endothelium. Figure 2 provides an overview of the pathways discussed in this chapter.