The aim of this review is to provide the current state of knowledge about the usefulness of modern genetic technologies in uncovering the causality of isolated and multiple congenital anomalies. Array comparative genomic hybridization and next-generation sequencing have revolutionized the clinical approach to patients with these phenotypes. Both technologies enable early diagnosis, especially in clinically challenging newborn populations, and help to uncover genetic defects associated with various phenotypes. The application of both complementary methods could assist in identifying many variants that may simultaneously be involved in the development of a number of isolated or multiple congenital anomalies. Both technologies carry serious variant misinterpretation risks as well. Therefore, the methods of variant classification and accessible variant databases are mentioned. A useful strategy of clinical genetic testing with the application of both methodologies is presented. Finally, future directions and challenges are briefly commented on in this review.