Clinical practice guidelines are available for the evaluation and management of thyroid nodules and thyroid cancer. Nevertheless, there are uncertainties associated with these protocols due to genomic variations among patients and an incomplete evidence base. In addition, deviations from these protocols are due to physician bias and different levels of training. These shortcomings may eventually disappear as emerging technologies enter mainstream medicine. These interventions include (1) better risk stratification with the routine use of diagnostic molecular marker panels in the cytological analysis of thyroid fine-needle aspiration specimens as well as hybridized imaging modalities, (2) less aggressive therapies in low- and intermediate-risk thyroid cancer patients, and (3) molecular targeted therapy, pretargeted radioimmunotherapy, and novel minimally invasive surgical techniques in high-risk thyroid cancer patients.