Microhomology-mediated end joining (MMEJ) is a repair pathway for DNA double-strand breaks (DSBs) that uses microhomology sequences (5–25 bp) to generate deletions. It is distinct from homologous recombination (HR) and non-homologous end joining (NHEJ), and is associated with chromosome rearrangements and genetic variation. MMEJ is often used when NHEJ and other mechanisms fail, but recent studies show it can function even in the presence of functional NHEJ. MMEJ is involved in various cellular processes, including V(D)J recombination and class switch recombination, and is linked to genomic instability and cancer. It is also implicated in telomere fusions and chromosomal translocations. MMEJ involves end resection, single-strand annealing, flap processing, and ligation. Key proteins involved include MRX, Rad1-Rad10, and DNA ligases. MMEJ is regulated by various factors, including Ku proteins, PARP-1, and checkpoint kinases. It plays a role in genetic variation and disease, and its mechanisms are being studied to understand its role in cancer and other genomic disorders.Microhomology-mediated end joining (MMEJ) is a repair pathway for DNA double-strand breaks (DSBs) that uses microhomology sequences (5–25 bp) to generate deletions. It is distinct from homologous recombination (HR) and non-homologous end joining (NHEJ), and is associated with chromosome rearrangements and genetic variation. MMEJ is often used when NHEJ and other mechanisms fail, but recent studies show it can function even in the presence of functional NHEJ. MMEJ is involved in various cellular processes, including V(D)J recombination and class switch recombination, and is linked to genomic instability and cancer. It is also implicated in telomere fusions and chromosomal translocations. MMEJ involves end resection, single-strand annealing, flap processing, and ligation. Key proteins involved include MRX, Rad1-Rad10, and DNA ligases. MMEJ is regulated by various factors, including Ku proteins, PARP-1, and checkpoint kinases. It plays a role in genetic variation and disease, and its mechanisms are being studied to understand its role in cancer and other genomic disorders.