While our understanding of cystic fibrosis genetics has expanded in recent decades, the genetics and clinical manifestations of the disease remains highly heterogeneous. Diagnosis of CF in non-classical mutations remains a clinical challenge. We describe the clinical presentation of two patients with chronic cough found to have normal sweat chlorides. We discuss the subsequent evaluation that lead to the diagnosis of two rare CF mutations. We briefly discuss the use of the expanded 106-panel of CF mutations (homozygous 3849 + 10 kb C > T), and the role of whole CFTR gene sequencing (heterozygous c.2752-26 A > G/5T).