CFTR modulators (CFTRm) were introduced recently but they are already profoundly changing Cystic Fibrosis (CF) landscape. This survey was conducted in 2018 to evaluate how their perception and use evolved in Italy, with focus on factors that could influence physician treatment decisions. Response rate was 75.6% and the majority of physicians (81%) had been working in CF for over 5 years. While traditional parameters such as lung function and nutritional status remain key evaluation criteria in relation to initiation and monitoring of CFTRm, pulmonary exacerbations ranked at least at the same level of importance in both pediatric and adolescent/adult patients homozygous for F508del, as well as those with residual function mutations. Increasing interest is shown for tools that can help detect early manifestations of disease such as Lung Clearance Index and imaging. Patient-related outcomes, such as ability to conduct daily activities, are also deemed relevant in decision to start and continue CFTRm. Physician decision to initiate treatment according to clinical presentation was similar in all groups, showing that more importance was given to severity/instability of disease rather than mutation type or age range. A relatively low percentage of physicians would treat asymptomatic patients, in particular very young or those with residual function mutations, showing reluctance to treat early in some patient groups in the absence of clear manifestations of CF. Increasing experience with CFTRm will allow to gain more long term evidence and will help shape new guidelines.