Von Willebrand disease (VWD) is the most common congenital bleeding disorder, but no single test to diagnose VWD nor predictors of VWD bleeding severity exist. While the 2021 evidence-based ASH ISTH NHF WFH guidelines for VWD diagnosis (James et al. Blood Adv 5:280–300, 2021) include 11 recommendations to aid in VWD diagnosis, it is noteworthy a diagnosis of VWD remains difficult for a number of reasons: (1) von Willebrand factor (VWF) levels alone may be insufficient unless they are supplemented by a bleeding assessment tool such as the BAT; (2) changes in VWF levels over time may require repeat testing; and (3) genetic mutations, while diagnostically helpful in type 2 and 3 VWD, are not found in half of those with type 1 VWD (James et al. Blood Adv 5:280–300, 2021; Goodeve et al. Blood 109:112–121, 2007; Goodeve et al. Haemophilia 20 Suppl 4:50–53, 2014; Lillicrap Blood 122:3735–3740, 2013). Further, it is recognized that mucosal bleeding symptoms typical of VWD, such as bruising, epistaxis, and menorrhagia, are common in the general population. Newer assays based on the platelet-binding aspects of VWF, including platelet-dependent VWF glycoprotein IbM (VWF:GPIbM) (Hubbard and Haberichter J Thromb Haemost 17:1003–1005, 2019), may provide additional diagnostic support for equivocal VWF ristocetin cofactor (VWF:RCo) activity, although both may be affected by acute phase reactants. Future efforts to improve VWD diagnosis should address the lack of standardization and assay and cutoff variability.