Array-based comparative genomic hybridization is ushering in a new standard for analyzing the genome, overcoming the limits of resolution associated with conventional G-banded karyotyping. The first genomic arrays were based on bacterial artificial chromosome clones mapped during the initial phases of the Human Genome Project. These arrays essentially represented multiple fluorescence in situ hybridization assays performed simultaneously. The first arrays featured a targeted design, consisting of hundreds of bacterial artificial chromosome clones limited mostly to genomic regions of known medical significance. Then came whole-genome arrays, which contained bacterial artificial chromosome clones from across the entire genome. More recently, alternative designs based on oligonucleotide probes have been developed, and all these are high-density whole-genome arrays with resolutions between 3 and 35 kb. Certain clinical circumstances are well suited for investigation by targeted arrays, and there are others in which high-resolution whole-genome arrays are necessary. Here we review the differences between the two types of arrays and the clinical contexts for which they are best suited. As array-based comparative genomic hybridization is integrated into diagnostic laboratories and different array designs are used in appropriate clinical contexts, this novel technology will invariably alter the testing paradigm in medical genetics and will lead to the discovery of novel genetic conditions caused by chromosomal anomalies.