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Screening for critical congenital heart disease (CCHD) at 24 to 48 hours after birth or before discharge in newborn nurseries using pulse oximetry is effective and is mandated by most states. However, there is no established protocol for screening in a neonatal intensive care unit (NICU), a setting where neonates are continuously monitored by pulse oximetry, hypoxemia from noncardiac causes is common, and echocardiograms are frequently obtained. CCHDs with hypoxemia are suspected on admission and investigated with an echocardiogram before a formal screen in the NICU. The most common CCHD lesions missed in a NICU setting are secondary targets of the screen, such as aortic arch anomalies (coarctation or interrupted aortic arch). The sensitivity of the current pulse oximeter-based CCHD screen to diagnose aortic arch anomalies is low. Given that infants are monitored with continuous pulse oximetry and frequent examinations, novel revisions to the current screening methods are necessary to detect asymptomatic NICU infants with aortic arch anomalies before discharge. Exclusions (whom to screen), technique (how to screen), and timing (when to screen) for primary and secondary targets of CCHD in the NICU are not known and require further research.