Current prenatal cytogenetic diagnosis uses mostly G-banded karyotyping of fetal cells from chorionic villi or amniotic fluid cultures, which readily detects any aneuploidy and larger structural genomic rearrangements that are more than 4 to 5 megabases in size. Fluorescence in situ hybridization (FISH) is also used for rapid detection of the common aneuploidies seen in liveborns. If there is prior knowledge that increases risk for a specific deletion or duplication syndrome, FISH with a probe specific for the region in question is done. Over the past decade, array-based comparative genomic hybridization (aCGH) has been developed, which can survey the entire genome for submicroscopic microdeletions and microduplications, in addition to all unbalanced chromosomal abnormalities that are also detected by karyotype. aCGH in essence interrogates the genome with thousands of probes fixed on a slide in a single assay, and has already revolutionized cytogenetic diagnosis in the pediatric population. aCGH is being used increasingly for prenatal diagnosis where it is also beginning to make a significant impact. The authors review here principles of aCGH, its benefits for prenatal diagnosis and associated challenges, primarily the inability to detect balanced chromosomal abnormalities and a small risk for discovery of chromosomal abnormalities of uncertain clinical significance. The superior diagnostic power of aCGH far outweighs these concerns. Furthermore, such issues can be addressed during pre- and posttest counseling, and their impact will further diminish as the technology continues to develop and experience with its prenatal diagnostic use grows.