Nearly 2,000 disease-causing mutations in CFTR, a 27-exon gene on chromosome 7,9‐11 have been identified. Although racial and ethnic differences exist, the most common mutation is c.1521_1523delCTT, or delF508, which accounts for > 70% of mutant alleles in the CF population.11,12 Mutations are usually grouped into six classes based on the protein product. Class 1 mutations consist of frameshift or nonsense variants that cause altered or impaired CFTR transcription, producing either messenger RNA that decays before nuclear export or truncated, nonfunctional protein. Class 2 mutations, such as delF508, result in misfolded protein that is trafficked to degradation pathways, has abnormal function, and is more rapidly cleared from the cell membrane. Mutations from both of these classes typically lead to more severe lung disease and pancreatic insufficiency. Class 3 mutations, including G551D, commonly called gating mutations, lead to a CFTR that is poorly responsive or nonresponsive to ATP activation of the nucleotide-binding domains, resulting in defective chloride conductance across the apical cell membrane. The clinical phenotypes and severity associated with class 3 mutations vary. Class 4, or conducting, mutations have impaired chloride conductance or transport caused by alterations in size and ion selectivity of the channel pore. Class 5 mutations are frequently splice mutants that reduce the rate of synthesis of functional CFTR and include intron 8 polythymidine variants. Class 6 mutations involve genetic defects that are near the N- or C-terminus and lead to aberrant membrane insertion, stability, or trafficking (Fig 2).2,6,13‐18 Some mutations defy classification. For instance, delF508 acts as a class 2 (altered processing), class 3 (impaired gating), and class 6 (rapidly degraded) mutation, which potentially has implications for molecular therapy. Other mutations are yet to be classified, either because of rarity of incidence or unclear effect on CFTR function.