Insights into the arms race between bacteria and invading mobile genetic elements have revealed the intricacies of the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas system and the counter-defenses ofbacteriophages. Incredible spacer diversity but significant spacer conservation among species/subspecies dictates the specificity of the CRISPR-Cas system. Researchers have exploited this feature to type/subtype the bacterial strains, devise targeted antimicrobialsand regulate gene expression. This review focuses on the nuances of the CRISPR-Cas systems in Enterobacteriaceae that predominantly harbortype I-E and I-F CRISPR systems. We discuss the systems'regulation by the global regulators, H-NS, LeuO, LRP, cAMP receptor proteinand other regulators in response to environmental stress. We further discuss the regulation of noncanonical functions like DNA repair pathways, biofilm formation, quorum sensingand virulence by the CRISPR-Cas system. The review comprehends multiple facets of the CRISPR-Cas system in Enterobacteriaceae including its diverse attributes, association with genetic features, regulation and gene regulatory mechanisms.