Fibrinogen is an abundant plasma protein that, when converted to fibrin by thrombin, provides the main building blocks for the clot. Dys-, a-, and hypo-fibrinogenemias have been variably linked to a normal phenotype, bleeding or even thrombosis. Meanwhile, increased fibrinogen concentrations in the blood have been associated with risk for thrombosis. More recently, studies have focussed on abnormal fibrin structure as a cause for thrombosis. Fibrin clots that have high fiber density and increased resistance to fibrinolysis have been consistently associated with risk for thrombosis. Fibrin structure measurements can (i) provide an overall assessment of hemostatic capacity of a sample, (ii) include effects of thrombin generation and fibrinogen concentrations, (iii) include effects of fibrinogen mutations, polymorphisms, and modifications, and (iv) give an indication of clot mechanical strength and resistance to fibrinolysis. A fibrinogen splice variation of the γ-chain (γ') is discussed as a model for changes in fibrin structure in relation to thrombosis. Results from prospective studies on fibrin structure are awaited. Studies of fibrin formation under flow, interactions of fibrin with blood cells, the mechanical properties of the fibrin clot, and nanoscale/molecular characterization of fibrin formation are likely to expose new causal mechanisms for the role of fibrin in thrombotic disease. Future studies into the causality and mechanisms may lead to new opportunities using fibrin structure in the diagnosis or treatment of thrombosis.