Cystic fibrosis is a severe autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) encoding the CFTR protein, a chloride channel expressed in many epithelial cells. New drugs called CFTR modulators aim at restoring the CFTR protein function and they will benefit most of the patients with cystic fibrosis in the near future. However, more than 10% of CFTR mutations do not produce any CFTR protein for CFTR modulators to act upon, and the purpose of this review is to provide an overview of different approaches pursued to treat patients bearing mutations nonresponsive to CFTR modulators. These different approaches constitute readthrough agents for nonsense mutations, nucleic acid-based therapies, RNA-based or DNA-based, and cell-based therapies. Some approaches using mRNA or cDNA combined with a delivery vehicle are mutation-agnostic therapies. Other approaches, such as the use of tRNA, antisense oligonucleotides, gene editing or cell-based therapies are mutation-specific therapies. Most of these approaches are in preclinical development or for some of them, early clinical phases. Many hurdles and challenges will have to be solved before they can be safely translated to patients.