The discovery of thyroid nodules in the general population has risen markedly with the greater use of ultrasound resulting in increasing use of ultrasound-guided fine needle aspiration (FNA) biopsy. Although FNA can identify the majority of nodules as either benign or malignant, one-third of aspirates demonstrate indeterminate cytologic characteristics. Though most of these nodules will be pathologically benign, thyroid surgery has usually been needed to make an accurate diagnosis, and the extent of surgery needed (lobectomy versus total thyroidectomy) is difficult to predict in advance. New molecular techniques are being investigated and used clinically to improve decision making in patients with thyroid nodules with indeterminate cytology. These molecular markers have the potential to help clinicians decide which patients may be monitored without thyroid surgery, and also the optimal strategy when surgery is felt to be necessary.