The correct diagnosis and classification of von Willebrand disease (vWD) is crucial because the presenting biological activity of von Willebrand factor (vWF) determines both the hemorrhagic risk and the subsequent clinical management. A variety of laboratory assays may be employed, not necessarily restricted to assessments of vWF. This article discusses the relative strengths and limitations of various functional or discriminatory vWF assays with a special focus on the vWF:collagen-binding activity (vWF:CBA) assay. This is a functional vWF assay that relies on the property of vWF adhesion to collagen. The vWF:CBA was first described approximately 15 years ago. The journey from that time point has been an interesting one, and the vWF:CBA is now gaining more widespread acceptance. There are now many published studies confirming the superiority of the vWF:CBA over the vWF ristocetin cofactor (vWF:RCof) activity as a functional screening diagnostic test process for vWD. However, both tests may be required in order to appropriately diagnose all forms of vWD. The relationship of these assays with multimer analysis is also discussed. In summary, an optimized vWF:CBA detects primarily high-molecular-weight (HMW) vWF forms and probably only about 30% of the total plasma vWF pool detected by vWF antigen (vWF:Ag). Because these HMW vWF forms are missing in types 2A and 2B vWD, the vWF:CBA is extremely useful in the detection of these qualitative vWD subtypes. In addition, however, concordance of vWF:CBA with vWF:Ag in unison with low vWF levels may alternatively suggest a type 1 vWD, and an absence of both vWF:Ag and vWF:CBA will suggest type 3 vWD. The vWF:CBA is also being investigated in various disease states, as is its usefulness as an effective marker of functional HMW vWF in both desmopressin (DDAVP) and factor-concentrate therapy in vWD.