INTRODUCTION: The clinical management of the inherited bleeding disorder von Willebrand disease (VWD) focuses on normalizing circulating levels of von Willebrand factor (VWF) and factor VIII (FVIII) to prevent or control bleeding events. The heterogeneous nature of VWD, however, complicates effective disease management and development of universal treatment guidelines. AREAS COVERED: The current treatment modalities of VWD and their limitations are described and why this prompts the development of new treatment approaches. In particular, RNA-based therapeutics have gained significant interest because of their ability to reversibly alter gene expression with long-term efficacy. In the field of VWD, small-interfering RNAs (siRNAs) have been explored through various strategies to improve disease phenotypes. These different approaches are discussed as well as their potential impact on reshaping the future therapeutic landscape. EXPERT OPINION: Current treatments for VWD often require frequent intravenous administration of VWF concentrates or desmopressin, with only short-term benefits. Moreover, remaining circulating mutant VWF can cause detrimental effects. Allele-selective siRNA-based therapies could provide more reliable and long-term disease correction by specifically targeting mutant