DNA double-strand breaks (DSBs) are critical for processes like meiotic recombination and immune system development but must be repaired accurately to maintain genome stability. Two primary repair pathways, homologous recombination (HR) and non-homologous end joining (NHEJ), efficiently repair DSBs. Recently, a third, less characterized repair mechanism, microhomology-mediated end joining (MMEJ), has gained attention. MMEJ uses substantial microhomology (5-25 bp) to repair DSBs, often resulting in deletions. It is associated with chromosome abnormalities and genetic variation in humans. This review summarizes genetic attributes of MMEJ from various model systems, discusses its relationship with 'alternative end joining,' and proposes a mechanistic model. MMEJ is robust in certain contexts, such as class switch recombination and V(D)J recombination, and can operate even in the presence of intact NHEJ and HR pathways. The review highlights the need to understand MMEJ's role in overall DSB repair, its regulation, and its implications for chromosome instability and cancer.DNA double-strand breaks (DSBs) are critical for processes like meiotic recombination and immune system development but must be repaired accurately to maintain genome stability. Two primary repair pathways, homologous recombination (HR) and non-homologous end joining (NHEJ), efficiently repair DSBs. Recently, a third, less characterized repair mechanism, microhomology-mediated end joining (MMEJ), has gained attention. MMEJ uses substantial microhomology (5-25 bp) to repair DSBs, often resulting in deletions. It is associated with chromosome abnormalities and genetic variation in humans. This review summarizes genetic attributes of MMEJ from various model systems, discusses its relationship with 'alternative end joining,' and proposes a mechanistic model. MMEJ is robust in certain contexts, such as class switch recombination and V(D)J recombination, and can operate even in the presence of intact NHEJ and HR pathways. The review highlights the need to understand MMEJ's role in overall DSB repair, its regulation, and its implications for chromosome instability and cancer.