The Bethesda system for standardized reporting of thyroid fine needle aspiration (FNA) cytology has positively affected the clarity of communication of results and management of patients evaluated for thyroid nodules. Problematic areas still exist in the triage of some of these samples, particularly those in the categories of “follicular lesion with atypia of uncertain significance” and “follicular lesion.” The literature on molecular and genetic abnormalities in thyroid lesions is reviewed. Potentially useful markers for distinguishing currently problematic categories of FNA cytologic samples, especially nondiagnostic samples, atypia of uncertain significance, and follicular lesions, are discussed. The predictive value of the respective molecular analyses in these settings is examined. Evaluation of FNA samples with negative or suboptimal follicular cytology for Ras mutations may be useful in detecting potentially significant follicular lesions (carcinomas) but is quite low in overall yield. Cytologic samples with atypia of uncertain significance, which may include the possibility of papillary carcinomas, may be fruitfully evaluated using a panel of molecular tests for BRAF, RET/PTC, PAX8/PPARG1, and Ras. Other markers also have potential utility in the workup of thyroid lesions. An era of combined modality testing in thyroid cytology is emerging in which classical cytologic findings can be coupled with molecular data to increase the predictive power of diagnostic interpretations; however, there remains a group of atypical cytologic samples negative for known molecular markers in which the risk of malignancy is too high to simply follow expectantly. Cancer (Cancer Cytopathol) 2012. © 2011 American Cancer Society.