Cystic fibrosis (CF) is the most common life-shortening genetic disease affecting approximately 1 in 3500 of the Caucasian population. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. To date, over 2000 CFTR mutations have been identified and produce a wide range of phenotypes. The CFTR protein, a chloride channel, is normally expressed on epithelial cells lining the lung, gut, and exocrine glands. Mutations in CFTR have led to pleiotropic effects in CF patients and have resulted in early morbidity and mortality. Research has focused on identifying small-molecules, or modulators, that can restore CFTR function. In recent years, two modulators, Ivacaftor (Kalydeco®) and Lumacaftor/Ivacaftor (Orkambi®), have been FDA-approved to treat CF patients with certain CFTR mutations. The development of these modulators has served as proof-of-concept that targeting CFTR by modulators is a viable therapeutic option. Efforts to discover new modulators that could deliver a wider and greater clinical benefit are still ongoing. However, traditional randomized controlled trials (RCTs) require large numbers of patients and become impracticable to test the modulators' efficacy in CF patients with CFTR mutations at frequencies much lower than 1%, suggesting the need for personalized medicine in these CF patients. This review provides an overview of recent advances in the development of CFTR modulators, including those approved for clinical use and ones in various stages of development. Moreover, we summarize several CF cases with rare CFTR mutations and highlight the significance of personalized medicine in finding effective therapeutic options for these patients.