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Simple Summary: One of the most powerful gene editing approaches is the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated) tool. The silkworm (Bombyx mori) has a great impact on the global economy, playing a pivotal role in the sericulture industry. However, B. mori came into the spotlight by representing one of science's greatest contributors, being used to establish extraordinary bioreactors for the production of target proteins and illustrating a great experimental model organism. Herein, we focus on progress made in the field of B. mori's genome manipulation by using CRISPR-Cas. In order to edit B. mori's genome, remarkable advances were made, such as exposing gene functions and developing mutant lines that exhibit enhanced resistance against B. mori nucleopolyhedrovirus (BmNPV). We also discuss how CRISPR-Cas accelerated the fundamental investigation in B. mori, and beyond, thus highlighting the great potential of the insect's biotechnology in numerous scientific fields. CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated) represents a powerful genome editing technology that revolutionized in a short period of time numerous natural sciences branches. Therefore, extraordinary progress was made in various fields, such as entomology or biotechnology. Bombyx mori is one of the most important insects, not only for the sericulture industry, but for numerous scientific areas. The silkworms play a key role as a model organism, but also as a bioreactor for the recombinant protein production. Nowadays, the CRISPR-Cas genome editing system is frequently used in order to perform gene analyses, to increase the resistance against certain pathogens or as an imaging tool in B. mori. Here, we provide an overview of various studies that made use of CRISPR-Cas for B. mori genome editing, with a focus on emphasizing the high applicability of this system in entomology and biological sciences. [ABSTRACT FROM AUTHOR]