For historical reasons, the sweat test remains the cornerstone in the diagnostic work-up for cystic fibrosis (CF). If CF is suspected, the sweat test (following pilocarpine iontophoresis) is usually performed first to confirm or rule out the diagnosis of CF. Sweat testing, however, is cumbersome to the patient, prone to technical difficulties and unreliable in young children < 4 weeks as well as in adults because of increasing chloride concentrations with age. False-positive and false-negative results do exist. Simple DNA testing with PCR in peripheral blood for a small number of the most common mutations causing CF, notably the delta F508-mutation in the Dutch population, rules out CF with a likelihood of more than 99%. Because of the high negative predictive value of DNA testing, in combination with its speed, reliability and convenience for the patient, starting the diagnostic work-up for CF with DNA testing can be justified in hospitals which possess the laboratory facilities for this type of test.