Identifying safe and effective therapies that target the underlying cause of cystic fibrosis remains a key priority for the cystic fibrosis community. CFTR modulators are first-in-class, regulatory-approved therapies that improve the function of the protein encoded by the CFTR gene and are associated with dramatic and sustained clinical benefits. Although approximately 90% of the population with cystic fibrosis could benefit from these therapies based on genetic eligibility, a crucial unmet need remains: developing CFTR-directed therapies for the ultra-rare population with cystic fibrosis who are not candidates for CFTR modulators due to either ineligibility or intolerance. Addressing this unmet need will depend on the clinical advancement of nucleic acid-based therapies (NABTs), a term that includes variant-specific antisense oligonucleotide therapies and variant-agnostic mRNA and DNA-based gene therapies. The clinical development of NABTs for those who are not candidates for or unable to take CFTR modulators is challenged not only by the relatively small target population, which affects feasible trial sizes, but also by unique regulatory requirements for long-term safety follow-up and the potential yet unknown short-term and long-term risks with genetic therapy cross-exposure or re-exposure. This Personal View addresses the proactive planning needed to maximise trial opportunities for the population who are not candidates for CFTR modulators, including considerations for subsequent NABT trial participation following previous NABT exposure.