Inborn errors of metabolism are generally categorized as rare diseases. Their presentations are often so subtle and insidious as to cause daunting diagnostic challenges for even the most astute clinicians. Thus, irreversible morbidity and preventable mortality have been unavoidable until recent decades because of delayed diagnoses. This unfortunate circumstance has led to newborn screening programs worldwide for 40 or more hereditary metabolic disorders beginning with the dramatic improvements for patients with phenylketonuria in the 1960's. Increasingly sophisticated testing procedures such as tandem mass spectrometry and other multiplex technologies applied to dried blood spot specimens are now having greater impact without raising costs significantly. The advent of next generation sequencing methods is likely to stimulate further progress and lead to whole genome or exome sequencing as prenatal and neonatal screening expands further. With early diagnosis through screening and expedited therapies better outcomes are routinely possible, and even preventive therapies amounting to “cures” can be anticipated through research.