In assessing a patient with excessive uterine bleeding, the clinician should consider systemic causes in the differential diagnosis. Both hereditary and acquired conditions can result in mucous membrane bleeding, including menorrhagia, epistaxis, and gum bleeding, as well as excessive bruising. Among hereditary conditions, von Willebrand disease (vWD) is by far the most common, affecting an estimated 1% of the population worldwide. It is important to consider the possibility of vWD, and to establish the proper diagnosis (including subtype), as safe, effective, and easy-to-use treatment is available for most persons with this disorder. This review also covers a number of other systemic conditions that can be manifested by excessive uterine bleeding, including congenital deficiency of factor XI, idiopathic thrombocytopenic purpura and other acquired platelet disorders, acquired autoantibodies against factor VIII (FVIII), and vitamin K deficiency states.