The plasma protein fibrinogen is encoded by 3 structural genes (FGA, FGB, and FGG) that are transcribed to mRNA, spliced, and translated to 3 polypeptide chains (Aα, Bβ, and γ, respectively). These chains are targeted for secretion, decorated with post-translational modifications, and assembled into a hexameric "dimer of trimers" (AαBβγ)₂ . Fully assembled fibrinogen is secreted into the blood as a 340 kDa glycoprotein. Fibrinogen is one of the most prevalent coagulation proteins in blood, and its expression is induced by inflammatory cytokines, wherein circulating fibrinogen levels may increase up to 3-fold during acute inflammatory events. Abnormal levels of circulating fibrinogen are associated with bleeding and thrombotic disorders, as well as several inflammatory diseases. Notably, therapeutic strategies to modulate fibrinogen levels have shown promise in experimental models of disease. Herein, we review pathways mediating fibrinogen synthesis, from gene expression to secretion. Knowledge of these mechanisms may lead to the identification of biomarkers and new therapeutic targets to modulate fibrinogen in health and disease.