Cystic fi brosis is caused by mutations in the cystic fi brosis transmembrane regulator (CFTR) gene which encodes an epithelial anion channel and regulatory protein. Derangements of CFTR protein function result in thickened, viscous mucus in the airways, GI tract, pancreas, sweat gland, and reproductive tract. The diagnosis and prognosis of CF is facilitated by demonstrating functional decrements of CFTR activity, and is a cornerstone of the diagnostic criteria. This chapter details the conduct and interpretation of the two most widely available diagnostic tests for CFTR functional analysis: sweat chloride testing and nasal potential difference (NPD). Details regarding the methods for conduct of these tests, sources of error, and emerging results supporting their interpretation are discussed.