Multiple cystic fibrosis (CF) testing platforms, using diverse and rapidly evolving technologies, are available to clinical laboratories commercially or for evaluation. Considerations when choosing a CF platform may include: sensitivity, specificity, accuracy, signal discrimination, ability to genotype, ability to reflex test, no calls/repeat rate, composition of mutation panel, hands-on time, start-to-finish time, integration into laboratory workflow, data analysis methods, flexibility regarding custom test design, and required instrumentation. Mindful of these considerations, we evaluated five technologically diverse CF platforms: 1) eSensor, an electronic detection assay system; 2) InPlex, a signal amplification methodology using a microfluidics card; 3) oligonucleotide ligation assay, an electrophoretic-based separation of amplicon-derived ligation-generated products; and two liquid bead arrays; 4) Signature, a direct hybridization assay using allele-specific capture probes; and 5) Tag-It, an assay using allele-specific primer extension and a universal microarray. A core of 150 samples, focusing on mutations in the American College of Medical Genetics/American College of Obstetricians and Gynecologists mutation panel, was tested throughout several runs for each platform. All of the platforms performed comparably in respect to sensitivity, specificity, and no-call rate. As our results indicate, consideration of all of the parameters evaluated may be useful when selecting the most appropriate platform for the specific setting.