This therapy, known also as highly effective modulator therapy (HEMT), realized a real paradigm shift in the management of CF as these molecules target the upstream underlying defect of the disease permitting the treatment of patients with almost one copy of F508del-CFTR, the most common CF-causing mutation (found in ~90% of PWCF) [2,11]. The gene discussed is CFTR; the disease is cystic fibrosis.