Thyroid carcinoma is the most common endocrine malignancy; it is typified by a number of classical genomic insults, which tend to cluster with the discrete histologic subtypes. The most common of these is a mutation in B-RAF, which is present in approximately 44% (29% to 83%) of cases. In this review we have assessed the potential utility of a molecular test for somatically acquired mutations in B-RAF using thyroid malignancy as a model system according to 3 fundamental questions: would a test enhance our ability to distinguish benign from malignant, would a test unveil a risk factor not otherwise known, and would detecting a mutation enable a therapeutic option specific to those patients who carry the mutation?