Usually, the human genome acquires one or fewer de novo genomic structural variants (SVs) per generation. However, in rare cases, multiple de novo SVs occur independently on different chromosomes. Typical examples are multiple de novo copy number variants (MdnCNVs) and multifocal genomic crises, collectively termed “multifocal genomic reconstruction.” MdnCNVs are characterized by multiple copy number gains on different chromosomes, which can be ascribed to replication-based errors. MdnCNV phenomenon is thought to persist during oogenesis and shortly after fertilization because of maternal factors that predispose oocytes and early embryos to genomic instability. In contrast, multifocal genomic crises result in various SVs such as deletions, duplications, inversions, and chromothriptic SVs, which are likely to be facilitated by replication-based errors and erroneous non-homologous repairs. Multifocal genomic crises appear to be restricted to spermatogenesis and may be influenced by several factors, such as paternal age, genetic background, and environmental exposures. Molecular methods useful for identifying multifocal genomic reconstruction include G-banding, multicolor fluorescence in situ hybridization, chromosomal microarray analysis, short- and long-read next-generation sequencing, and optical genome mapping. These analyses can identify undiscovered cases and lead to a better understanding of the basis of multifocal genomic reconstruction.