Disseminated intravascular coagulation (DIC) is a devastating clinical condition that is characterized by the loss of normal hemostatic control in response to sustained and systemic cell injury. The inciting injury may be from infection, trauma, or malignancy, but the consequent pathophysiology is multifactorial involving intertwined feedback loops between the coagulant, immune, and inflammatory pathways. Central to this is thrombin generation, but the ubiquitous nature of its in vivo functional consequences can make it difficult to dissect away the separate but overlapping components to the clinical problem. Therefore, early recognition and resolution of the precipitating events leading to DIC remains the central tenet to clinical care. This article refreshes our conceptual understanding of DIC pathogenesis and draws in recent advances in the cycle of cell death caused by extracellular nuclear proteins. It also aims to delineate recognition of response pathways that can be predominantly procoagulant or profibrinolytic to enable a more personalized and evidence-based approach to be delivered to the patient with DIC.