The semi-essential (SE) region of bacteriophage Mu, a 16-gene cluster within its 36717-base genome, is a poorly characterized segment hypothesized to confer fitness advantages to bacterial host under stress. Only four genes, kil, gam, gemA, and mor, are well-studied, while the 12 remaining open reading frames (ORFs) likely enhance host survival in hostile environments, such as nutrient scarcity or immune pressure. Prophages like Mu drive bacterial evolution by encoding traits like virulence and antibiotic resistance, making them pivotal for combating multidrug-resistant (MDR) bacteria. This mini-review analyses knowledge of the SE region's structure, functions, and role in host fitness, integrating genomic, and transcriptomic studies. We explore its therapeutic potential, particularly for phage therapy, and advocate for CRISPR-based approaches to elucidate uncharacterized SE genes, offering novel strategies to address the MDR crisis.