Ultrasound-detected structural anomalies have an impact on fetal mortality and morbidity. Prenatal Exome Sequencing is incorporated into clinical care pathways for paediatric populations but maybe used to delineate the prognosis of fetal structural anomalies. This paper reviews the literature defining the clinical utility of prenatal ES and discusses the potential promise and challenges for implementation of this technology into clinical practice. Prospective case selection with accurate and informative pre-test counselling by multidisciplinary, clinical genetic-led teams is imperative. Robust, regulated laboratory sequencing, informative bioinformatic pathways with variant identification and conservative matching with the phenotype (within clinical review panels) is also important.