: Complement and coagulation are evolutionarily related proteolytic cascades in the blood that are critical for effecting an appropriate innate response to injury that limits bleeding and infection, while promoting healing. Although often viewed as distinct, it has long been recognized that cross-talk likely exists between these pathways. Only recently have molecular links been established. These are providing insights that are revealing opportunities for the development of novel therapeutic strategies to better treat a wide range of thrombotic, inflammatory, immune, infectious, and malignant diseases. In this brief review, the complex relationship between complement and coagulation is highlighted, underlining some of the newly uncovered interactions, in the hopes of stimulating innovative research that will yield improvements in patient outcomes.