Fibrinogen (Fg) and its derivatives play a considerable role in many diseases. For example, increased levels of Fg have been found in many inflammatory diseases, such as Alzheimer’s disease, multiple sclerosis, traumatic brain injury, rheumatoid arthritis, systemic lupus erythematosus, and cancer. Although associations of Fg, Fg chains, and its derivatives with various diseases have been established, their specific effects and the mechanisms of actions involved are still unclear. The present review is the first attempt to discuss the role of Fg, Fg chains, its derivatives, and other members of Fg family proteins, such as Fg-like protein 1 and 2, in inflammatory diseases and their effects in immunomodulation.