The article reviews the mechanisms of copy number variation (CNV) in humans, which are significant sources of genetic diversity and are linked to various diseases. CNVs can arise through homologous recombination (HR) and non-homologous recombination (NHR). HR involves extensive DNA sequence identity and strand exchange proteins, while NHR uses microhomology or no homology. The authors discuss several HR mechanisms, including double Holliday junction and synthesis-dependent strand annealing (SDSA), and NHR mechanisms such as non-homologous end joining (NHEJ) and microhomology-mediated end joining (MMEJ). They propose that microhomology-mediated break-induced replication (MMBIR) is a major mechanism for most CNV formation, involving replication slippage and template switching under stress conditions. The article also highlights the role of chromosome architecture in CNV distribution and the potential implications of CNV for evolution, physiology, and disease.The article reviews the mechanisms of copy number variation (CNV) in humans, which are significant sources of genetic diversity and are linked to various diseases. CNVs can arise through homologous recombination (HR) and non-homologous recombination (NHR). HR involves extensive DNA sequence identity and strand exchange proteins, while NHR uses microhomology or no homology. The authors discuss several HR mechanisms, including double Holliday junction and synthesis-dependent strand annealing (SDSA), and NHR mechanisms such as non-homologous end joining (NHEJ) and microhomology-mediated end joining (MMEJ). They propose that microhomology-mediated break-induced replication (MMBIR) is a major mechanism for most CNV formation, involving replication slippage and template switching under stress conditions. The article also highlights the role of chromosome architecture in CNV distribution and the potential implications of CNV for evolution, physiology, and disease.