VP28 is an essential WSSV envelope protein used to develop innate immune recognition in shrimp against WSSV, owing to its remarkable capability to localize on the surface of shrimp epithelial cells. Transgenically engineered viral VP28 protein from several expression systems was used to increase the survival chances of shrimp against WSSV pathogen, and their efficacy was found to last for 2-3 weeks following therapy. Though few reports have shown that DNA vaccination using the VP28 DNA construct is capable of protecting shrimp from WSSV, the exact mechanism behind the immunity is still unknown. Several research groups have provided insights into VP28-driven dsRNA vaccination to protect shrimp against WSSV infection, but the stability attained by many of these vaccines turned out to be short-lived. RNAi treatment with VP28dsRNA, shrimp showed better resistance to the WSSV challenge, although multiple doses of dsRNA are required to provide extended protection for up to 28 days. However, no foolproof protection was currently offered by VP28-based recombinant protein or DNA vaccination against WSSV. In recent years, attention has been directed towards identifying small molecule inhibitors of VP28 through molecular docking and molecular dynamics simulation studies and is an emerging approach in drug development and design against WSSV. This review highlights the opportunities, limits and challenges of VP28-based control strategies of White Spot Syndrome Virus, by emphasizing the status quo of current methodological approaches and suggesting future research directions of using it as a potential drug discovery target.