The challenge of newborn screening programmes is to maximise benefits and minimise harms. These harms include pain inflicted as a result of taking the test, reduced by pain relief and training of specimen takers; from false positive and negative test results (impacting both affected families and healthcare professionals), minimised effectively by taking the sample at the correct time, precise and specific tests, appropriate disorder definition, well chosen cut-offs (which may be informed by a large series of diagnosed cases of the screened disorders) second-tier tests, age adjusted normal ranges and anxiety which may be appropriate but limited by the availability of information. Programme audit is important in early detection of problems.