The development of microarray-based comparative genomic hybridization (array CGH) methods represents a critical new advance in molecular cytogenetics. This new technology has driven a technical convergence between molecular diagnostics and clinical cytogenetics, questioned our naïve understanding of the complexity of the human genome, revolutionized the practice of medical genetics, challenged conventional wisdom related to the genetic bases of multifactorial and sporadic conditions, and is poised to impact all areas of medicine. The use of contemporary molecular cytogenetic techniques in research and diagnostics has resulted in the identification of many new syndromes, expanded our knowledge about the phenotypic spectrum of recognizable syndromes, elucidated the genomic bases of well-established clinical conditions, and refined our view about the molecular mechanisms of some chromosomal aberrations. Newer methodologies are being developed, which will likely lead to a new understanding of the genome and its relationship to health and disease.