Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have revolutionised cystic fibrosis (CF) care, leading to significant improvements in lung function, decreased frequency of pulmonary exacerbations and improved quality of life [1]. The list of variants eligible for CFTR modulators has increased over time, currently covering almost 90% of individuals with CF in Caucasian populations. For rare and poorly characterised CF-causing variants, ex vivo analysis of intestinal organoids may assess CFTR function and guide personalised therapy [2, 3]. We report the case of an individual with CF whose rectal organoids were used to evaluate response to CFTR modulators and to guide therapeutic decision. Ex vivo analysis of intestinal organoids has great translational potential as a precision medicine tool for the prediction of clinical efficacy of CFTR modulators and, for patients with rare variants, may hold the key to these life-changing therapies http://bit.ly/3G1FkDp