Copy number variation (CNV) is a major source of genetic variation among humans. In addition to existing as benign polymorphisms, CNVs can also convey clinical phenotypes, including genomic disorders, sporadic diseases and complex human traits. CNV results from genomic rearrangements that can represent simple deletion or duplication of a genomic segment, or be more complex. Complex chromosomal rearrangements (CCRs) have been known for some time but their mechanisms have remained elusive. Recent technology advances and high-resolution human genome analyses have revealed that complex genomic rearrangements can account for a large fraction of non-recurrent rearrangements at a given locus. Various mechanisms, most of which are DNA-replication-based, for example fork stalling and template switching (FoSTeS) and microhomology-mediated break-induced replication (MMBIR), have been proposed for generating such complex genomic rearrangements and are probably responsible for CCR.