In recent years, a tremendous amount of inquisitiveness among scientists in the clustered regularly interspaced short palindrome repeats (CRISPR)–CRISPR-associated proteins (Cas) has led to many studies to delineate their exact role in prokaryotes. CRISPR–Cas is an adaptive immune system that protects prokaryotes from phages and mobile genetic elements. It incorporates small DNA fragment of the invader in the CRISPR-array and protects the host from future invasion by them. In a few instances, the CRISPR-array also incorporates self-targeting spacers, most likely by accident or leaky incorporation. A significant number of spacers are found to match with the host genes across the species; however, self-targeting spacers have not been investigated in detail in most of the organisms. The presence of self-targeting spacers in the CRISPR-array led to speculation that the CRISPR–Cas system has a lot more to offer than just being the conventional adaptive immune system. It has been implicated in gene regulation and autoimmunity more or less equally. In this review, an attempt has been made to understand self-targeting spacers in the context of gene regulation, autoimmunity, and its avoidance strategies.