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Objective The development of a venous leg ulcer (VLU) represents the most severe clinical manifestation of a chronic venous disease. Despite major progress, our understanding of the VLU pathogenesis and wound healing biology has remained limited. Treatment of VLUs remains a serious challenge for physicians of different specialties. In the present review, we focused on describing the rationale and scientific basis for topical wound care in the management of VLUs. Methods A literature review was performed to summarize the methods with proven efficacy in VLU management. A systematic search was also performed to identify new evidence from the randomized controlled trials reported from 2014 to 2021. The scientific challenges, clinical practice concerns, economic obstacles, and possible directions for further research have been discussed. Results Hundreds of topical products have been advertised for the treatment of VLUs. However, the reported data on the topical treatment of venous ulcers are insufficient, scattered, and weak, with significant methodologic flaws. A total of 43 randomized controlled trials on the topical treatment of VLUs were reported from 2014 to 2021. Thus, the clinical practice guidelines require updating. We identified major gaps in knowledge and have provided suggestions for future research directions. Conclusions The American Venous Forum Research Committee would like to bring attention to the use of topical wound care for VLUs as a critical gap in knowledge and to encourage scientists, practitioners, and industry to collaborate to fill this gap.