2019 will be remembered as a landmark year for the Cystic Fibrosis (CF) community because it marks the year when effective modulator therapy became available for most CF patients[1-3]. effective modulator therapy has the potential to change the trajectory of patients’ health and long-term outcomes. These therapies optimize the function of the patients’ endogenous mutant Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), which results in return of CFTR channel function [1,2,4-6]. Although the combination of high throughput screening of small molecule libraries and medicinal chemistry have resulted in amazing new effective modulator therapies for many, it is unlikely that this approach will provide a game changing therapy for all. In part because the response to even the most promising modulator therapy is variable and an area of active investigation. Also, there are about 10% of patients with CF who don’t produce a mutant protein to modulate, potentiate or optimize and for these patients such therapies are unlikely to be of significant benefit. Efforts to develop small molecule therapy to promote protein production in patients with nonsense mutations such as PTC124 has proved to be far more challenging than predicted . There is a need to develop new therapeutic approaches that can work for this patient population. These new therapies will be genetic-based therapies that include ribonucleic acid (RNA) therapies, deoxyribonucleic acid (DNA) therapies and gene editing technologies. Each approach will result in functional CFTR expression in CF affected cells. Ideally, these approaches would require less frequent dosing than effective modulators, which are given daily. For instance, RNA based treatments could be given periodically. Ultimately, treatment with certain gene-altering treatments could be given once in a lifetime and lead to a permanent cure (Figure 1). In this review which is based on Plenary 1 from the North American Cystic Fibrosis Conference in 2019 which is based on Plenary 1 from the North American Cystic Fibrosis Conference in 2019 we will examine the potential of RNA therapies, gene transfer therapies and gene editing therapies for the treatment of CF[8-13], as well as the challenges that will need to be faced as we harness the power of these emerging therapies towards a one-time cure. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.