Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that results in abnormal viscous mucoid secretions in multiple organs and whose main clinical features are pancreatic insufficiency and chronic endobronchial infection. Although it was initially defined and diagnosed based on clinical features and sweat chloride measurement, an in vivo method of assessing CFTR function, the discovery of the CFTR gene in 1989 revealed a broad spectrum of CF phenotypes associated with specific CFTR gene mutations. In this article, we will review the indications for sweat testing, alternative techniques to diagnose CF, and the approach to patients with an ambiguous or indeterminate diagnosis of CF.