Cystic fibrosis is a monogenic genetic disease due to mutations in the gene coding for a membrane protein, the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR controls the flow of chloride ions through the apical membrane of epithelia, thus regulating the transepithelial movement of both water and ions, needed for the production of healthy secretions. Mutations in the CFTR gene affect the proper folding, trafficking and function of CFTR, resulting in the formation of thick and viscous mucus that accumulates in different organs, notably in the lungs where it predisposes to persistent bacterial infections.CFTR belongs to the ATP binding cassette (ABC) transporter superfamily. Human ABC transporters share a common structural architecture, which minimally consists of two transmembrane domains (TMDs), forming in CFTR the pore for chloride flow, and two nucleotide binding domains (NBDs), for ATP binding and hydrolysis.The lack of crystal structures hampers a global understanding of the structure and function of CFTR, and thus the development of approaches directly targeting defective CFTR. Here, we present molecular models of CFTR in different conformational states, built on available structural data. We focus in particular on closed state conformations, and on the interactions at the NBD interface. The models are used, together with available experimental data, to infer the roles played by specific residues in the gating transitions, allowing hypothesis testing through mutagenesis and functional studies.