This perspective reviews the advancements in genome technology over the past 25 years and their impact on the discovery of germline variants in human genetics. The field has evolved from chromosomal microarrays (CMAs) for detecting copy number variants (CNVs) to short-read sequencing (SRS) for identifying single-nucleotide variants (SNVs), and now to long-read sequencing (LRS) for resolving complex structural variants (SVs). Each technology has provided access to different classes of human genetic variation, with LRS offering the promise of comprehensive variant detection in a single assay. The transition to LRS is expected to transform our understanding of human health and biology, particularly in uncovering the dynamic mutational processes shaping our genomes. The article highlights the importance of CNVs in neurodevelopmental disorders and the role of *de novo* mutations in neuropsychiatric conditions. It also discusses the limitations of SRS in detecting SVs within repetitive regions and the advantages of LRS in traversing these regions. The completion of the first telomere-to-telomere (T2T) human genome and the development of the human pangenome reference have enabled more systematic studies of inversion polymorphisms, interlocus gene conversion (IGC), and ectopic exchanges between acrocentric short arms. The article concludes by discussing the future directions, including the potential of personalized reference genomes and the challenges in clinical adoption and computational processing.This perspective reviews the advancements in genome technology over the past 25 years and their impact on the discovery of germline variants in human genetics. The field has evolved from chromosomal microarrays (CMAs) for detecting copy number variants (CNVs) to short-read sequencing (SRS) for identifying single-nucleotide variants (SNVs), and now to long-read sequencing (LRS) for resolving complex structural variants (SVs). Each technology has provided access to different classes of human genetic variation, with LRS offering the promise of comprehensive variant detection in a single assay. The transition to LRS is expected to transform our understanding of human health and biology, particularly in uncovering the dynamic mutational processes shaping our genomes. The article highlights the importance of CNVs in neurodevelopmental disorders and the role of *de novo* mutations in neuropsychiatric conditions. It also discusses the limitations of SRS in detecting SVs within repetitive regions and the advantages of LRS in traversing these regions. The completion of the first telomere-to-telomere (T2T) human genome and the development of the human pangenome reference have enabled more systematic studies of inversion polymorphisms, interlocus gene conversion (IGC), and ectopic exchanges between acrocentric short arms. The article concludes by discussing the future directions, including the potential of personalized reference genomes and the challenges in clinical adoption and computational processing.