The common life-limiting genetic disease cystic fibrosis (CF) is caused by mutations in the ATP-binding cassette transporter cystic fibrosis transmembrane conductance regulator (CFTR). Expressed in the apical membrane of epithelia, CFTR functions as a Cl- channel with complex regulation to control the hydration of epithelial surfaces lining ducts and tubes throughout the body. To date, almost 2,000 mutations have been identified in the CFTR gene. Studies of the molecular mechanisms of CFTR dysfunction in CF have identified six different classes of mutation, which disrupt either the production of CFTR protein, its delivery to, and stability at the apical membrane or function as a regulated Cl- channel. Some CF mutations cause CFTR dysfunction by one mechanism only. For example, G551D disrupts channel gating without affecting protein processing and stability. However, other CF mutations cause CFTR dysfunction by multiple mechanisms. This is best illustrated by F508del, the most common CF mutation carried by almost 90% of CF patients. F508 is located on the surface of the first nucleotide-binding domain (NBD1), where it interacts with the coupling helix of intracellular loop 4 from membrane-spanning domain 2 (MSD2). Deletion of this phenylalanine residue causes a temperature-sensitive folding defect, which disrupts CFTR processing and intracellular transport to the apical membrane. Any F508del-CFTR that reaches the plasma membrane exhibits two further defects: protein instability and defective channel gating. Restoration of channel function to F508del-CFTR therefore requires at least two types of small molecules: (i) CFTR correctors designed to traffic misfolded F508del-CFTR protein to, and stabilise it at, the apical membrane and (ii) CFTR potentiators designed to enhance greatly channel activity by augmenting channel gating. One CFTR potentiator (ivacaftor) is now approved for clinical use with ten CF mutations, including G551D, transforming the lives of eligible CF patients. Clinical trials of ivacaftor and the CFTR corrector lumacaftor were completed last year in CF patients with the F508del mutation. This presentation will discuss the rescue of F508del-CFTR by CFTR correctors and potentiators. It will highlight the requirement for combinations of small molecules to fully restore function to F508del-CFTR Cl- channels.