Copy number variation (CNV) is a major source of genetic diversity in humans. Various genome analysis platforms, including array comparative genomic hybridization (aCGH), single nucleotide polymorphism (SNP) genotyping, and next-generation sequencing, have identified numerous CNVs. CNVs can arise through recombination-based and replication-based mechanisms, with de novo mutation rates being much higher than for SNPs. CNVs can cause Mendelian or sporadic traits, or be associated with complex diseases, but can also represent benign polymorphic variants. CNVs, especially gene duplication and exon shuffling, are significant drivers of gene and genome evolution. CNVs are widespread in human genomes and represent a significant source of genetic variation. Over 38,000 CNVs (>100 bp in size) and many other structural variations (SVs) have been reported. SVs may account for more differences among individuals than SNPs. CNVs have a much higher de novo mutation rate than SNPs. Mechanisms such as nonallelic homologous recombination (NAHR), nonhomologous end-joining (NHEJ), and retrotransposition are implicated in CNV formation. A novel replication-based mechanism, fork stalling and template switching (FoSTeS), has been proposed to account for complex genomic rearrangements. Breakpoint sequencing data also suggest that a portion of CNV occurs via a mechanism consistent with FoSTeS. CNVs are associated with human complex traits such as susceptibility to HIV infection, autism, and schizophrenia. CNVs can encompass part or all of a gene, or be a genomic segment containing several genes, and may alter human physiological functions. Human-specific CNVs may be responsible for advantageous traits such as cognition and endurance running. CNVs are subject to evolutionary pressures such as selection and genetic drift. CNVs include gene duplication and exon shuffling, which are predominant mechanisms driving gene and genome evolution. The Database of Genomic Variants (DGV) includes 38,406 SVs. CNVs can vary in size from single exons (≈100 bp) to millions of base pairs. The contributions of CNVs to human phenotypes, especially complex diseases, are still unknown. Recent studies suggest that CNVs can explain a significant portion of gene expression variation, with SNPs explaining a much larger portion. The number of CNVs yet to be discovered is large. Many sequence gaps in the human genome may contain SVs. Genomic regions with available reference sequences may still contain novel SVs. Complex LCRs provide structural basis for various variations, including duplication, deletion, and inversion. Detection of all SVs requires detailed analysis of many haplotypes. Complex LCRs can form cruciforms and trigger genomic rearrangements. Four major mechanisms generate rearrangements in the human genome: NAHR, NHEJ, FoSTeS, and L1-mediatedCopy number variation (CNV) is a major source of genetic diversity in humans. Various genome analysis platforms, including array comparative genomic hybridization (aCGH), single nucleotide polymorphism (SNP) genotyping, and next-generation sequencing, have identified numerous CNVs. CNVs can arise through recombination-based and replication-based mechanisms, with de novo mutation rates being much higher than for SNPs. CNVs can cause Mendelian or sporadic traits, or be associated with complex diseases, but can also represent benign polymorphic variants. CNVs, especially gene duplication and exon shuffling, are significant drivers of gene and genome evolution. CNVs are widespread in human genomes and represent a significant source of genetic variation. Over 38,000 CNVs (>100 bp in size) and many other structural variations (SVs) have been reported. SVs may account for more differences among individuals than SNPs. CNVs have a much higher de novo mutation rate than SNPs. Mechanisms such as nonallelic homologous recombination (NAHR), nonhomologous end-joining (NHEJ), and retrotransposition are implicated in CNV formation. A novel replication-based mechanism, fork stalling and template switching (FoSTeS), has been proposed to account for complex genomic rearrangements. Breakpoint sequencing data also suggest that a portion of CNV occurs via a mechanism consistent with FoSTeS. CNVs are associated with human complex traits such as susceptibility to HIV infection, autism, and schizophrenia. CNVs can encompass part or all of a gene, or be a genomic segment containing several genes, and may alter human physiological functions. Human-specific CNVs may be responsible for advantageous traits such as cognition and endurance running. CNVs are subject to evolutionary pressures such as selection and genetic drift. CNVs include gene duplication and exon shuffling, which are predominant mechanisms driving gene and genome evolution. The Database of Genomic Variants (DGV) includes 38,406 SVs. CNVs can vary in size from single exons (≈100 bp) to millions of base pairs. The contributions of CNVs to human phenotypes, especially complex diseases, are still unknown. Recent studies suggest that CNVs can explain a significant portion of gene expression variation, with SNPs explaining a much larger portion. The number of CNVs yet to be discovered is large. Many sequence gaps in the human genome may contain SVs. Genomic regions with available reference sequences may still contain novel SVs. Complex LCRs provide structural basis for various variations, including duplication, deletion, and inversion. Detection of all SVs requires detailed analysis of many haplotypes. Complex LCRs can form cruciforms and trigger genomic rearrangements. Four major mechanisms generate rearrangements in the human genome: NAHR, NHEJ, FoSTeS, and L1-mediated