Extended newborn screening (ENBS) with the use of tandem mass spectrometry technology is well established in all Australian states and in New Zealand. ENBS has afforded a marked reduction in morbidity and mortality in select conditions such as medium-chain acyl-CoA dehydrogenase deficiency. While this technology has been of great benefit to newborn screening, it comes with many inherent and unforeseen challenges. In this review, we discuss the successes and challenges associated with ENBS.