Inherited deficiency of FXIII A subunit (FXIII-A) is a rare (1:2,000,000) but very severe bleeding diathesis. The incidence is much higher in communities where the practice of consanguineous marriage is combined with founder effect mutation. Because of the high risk of intracranial bleeding, life-long prophylaxis, preferably using FXIII concentrate, is mandatory. In FXIII-B subunit deficiency the bleeding diathesis is mild to moderate. FXIII deficiency is frequently associated with impaired wound healing. Women suffering from FXIII deficiency cannot carry pregnancies to term; in severe cases spontaneous abortion occurs in the first trimester. Plasma-derived heat-inactivated FXIII concentrate and recombinant FXIII-A are available for prophylaxis; a 4 weekly dose of 35 to 40 U/kg is recommended and a trough level of greater than 5% FXIII activity should be aimed for. During pregnancy, 2 weekly prophylaxis with a target trough level of greater than 10% is recommended, and during labor FXIII activity should exceed 30%. During surgical procedures, the target should be higher than 50% FXIII activity. Alloantibodies make FXIII deficiency difficult to manage, but fortunately they are extremely rare. Acquired FXIII deficiency may involve both subunits. Autoantibodies against FXIII subunits also manifest in severe bleeding complication with a relatively high mortality rate. The first-line test in the diagnosis of FXIII deficiency should be a quantitative functional assay based on the measurement of ammonia release or amine incorporation. The sensitivity of the traditional clot solubility assay is not sufficiently robust to enable proper screening. Antigen assays are needed for the classification of FXIII deficiencies. In the case of anti-FXIII antibodies, the diagnostic armory should be supplemented by a mixing test/Bethesda-type inhibitor assay and by assays that detect/measure the binding of antibodies to FXIII and to its subunits.