Currently, available single and dual‐combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies have favorably altered the life course of individuals with cystic fibrosis (CF) by decreasing morbidities and increasing survival. However, even with CFTR modulator use, questions and challenges remain to optimize the management of lung infections. This review (a) identifies these ongoing challenges and discusses the current understanding of the potential impact of CFTR modulator therapy on infections; (b) describes ongoing research to optimize detection, diagnosis, and treatment of CF microorganisms; and (c) discusses strategies to develop new anti‐infective therapies. The CF Foundation has launched the Infection Research Initiative to fund research that will improve our understanding of the complex microbial ecology within the CF lung, improve detection of CF pathogens, optimize current treatment, including long‐term chronic therapies, and develop new anti‐infective therapies. Ongoing clinical trials to determine the optimal duration of treatment of pulmonary exacerbations and to diagnose and treat nontuberculous mycobacteria represent clinical research paradigms that could be used to answer other complex treatment questions. The anti‐infective pipeline includes both existing anti‐infective and non‐anti‐infective agents, many of which are proposed to have unique mechanisms of action in CF. Future studies plan to evaluate short‐ and long‐term clinical effectiveness and impact on infections, of the next generation of CFTR modulator therapy, the highly effective triple‐combination therapy, for individuals with CF, homozygous or heterozygous for F508del.