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Silkworm (Bombyx mori) is not only an economic insect but also a model organism for life science research. Bombyx mori nucleopolyhedrovirus (BmNPV) disease is a major infectious disease in the world's sericulture industry. The cocoon loss caused by this disease accounts for more than 60% of the total loss caused by all silkworm diseases. To date, there has been no effective solution for preventing and treating this disease. The most effective measure is to breed disease-resistant varieties. The quickest way to breed disease-resistant varieties is to apply genetic modification. However, this requires that we obtain disease resistance genes and know the mechanism of disease resistance. Since the discovery of disease-resistant resources in 1989, scholars in the sericulture industry around the world have been inspired to search for resistance genes. In the past two decades, with the help of multi-omics technologies, screening of resistance genes, gene localization, protein modification, virus–host interactions, etc., researchers have found some candidate genes that have been proposed to function at the cellular or individual level. Several disease-resistant varieties have been obtained and used in production through hybrid breeding, RNA interference, and genetic modification. This article summarizes and reviews the discovery of and research advances related to silkworm resistance to BmNPV. It is anticipated that the review will inspire scientific researchers to continue searching for disease resistance genes, clarify the molecular mechanism of silkworm disease resistance, and promote disease-resistant silkworm breeding. [ABSTRACT FROM AUTHOR]