Fine needle aspiration biopsy (FNAB) has aided in the diagnosis and management of thyroid nodules for decades. Now a rapid evolution is hoped to benefit an increasing cohort of patients with small nodules and non-diagnostic investigations. This review discusses the well-documented limitations of FNAB and the diagnostic utility of testing for somatic mutations and rearrangements found in thyroid cancer. Fine needle aspiration (FNA) with molecular alteration testing has high specificity and positive predictive value. FNA with gene expression has high sensitivity and negative predictive value and hopes to reduce the number of diagnostic thyroid lobectomies. Patients whose results are either follicular lesion of unknown significance or atypia of unknown significance may be the biggest beneficiaries as they frequently undergo diagnostic lobectomy that may be unnecessary, with associated healthcare costs and morbidity. Several mutations within the mitogen-activated protein kinase pathway have been documented in the development of papillary thyroid carcinoma, including RAS and BRAFV600E mutations and RET/PTC rearrangements. In follicular thyroid carcinoma and follicular adenoma, genetic mutations in the PI3K-AKT pathway are common. Well-differentiated thyroid cancer exhibits indolent behaviour but occasionally may behave in a very aggressive fashion. Prognostication using biomarkers may be a useful tool to guide the extent of initial surgery as BRAFV600E has been identified as an independent risk factor for the recurrence of papillary thyroid cancer and also death.