Metamorphosis is a development process involving the programmed cell death of obsolete larval organs. Aspartic proteinase cathepsin D (BmCatD) is involved in the silkworm Bombyx mori metamorphosis. Here we show a novel functional role of cysteine proteinase cathepsin B during B. mori metamorphosis. The B. mori cathepsin B (BmCatB) was expressed in the fat body, epidermis, ovary, testis, and hemocyte of the larval and pupal stages. The BmCatB was ecdysoneinduced, expressed in the fat body of the molting, the final larval instar and pupal stages, and its expression led to programmed cell death. RNA interference (RNAi)-mediated BmCatB knock-down inhibited the programmed cell death of larval and pupal fat body, resulting in the arrest of larval-pupal transformation. BmCatB RNAi is up-regulated the expression of BmCatD. Based on these results we concluded that BmCatB is critically involved in the histolysis of the larval and pupal fat body, indicating that BmCatB and BmCatD are mutally regulated during silkworm metamorphosis.