In this contribution, we review the limitations of the currently applied standard treatments for well-differentiated, non-medullary thyroid cancer (ThyrCa), and describe the molecular and cellular biologic basis of potential novel therapeutic modalities currently under study and / or development. Conventional therapy for ThyrCa consists of total / near-total thyroidectomy, radioiodine (RAI or 131I), and long-term thyroid hormone suppressive therapy (THST). RAI therapy remains the cornerstone of the standard management strategies for metastatic ThyrCa, and when administered under optimal conditions can achieve either eradication or long-term clinical control of the disease. Despite increasing sophistication in the protocols using 131I over the last 30 years, no significant down-trend has been observed in the annual mortality rate for this disease, a fact reflecting the existence of a core population of patients with RAI-resistant disease. The molecular basis for this phenomenon is believed to be the progressive tumoral de-differentiation over time, with loss of (or marked decrease in) the expression of cellular components responsible for iodine uptake, organification and retention. Adjuvant methods to RAI, such as radiosensitizers and lithium carbonate, provide only marginal additional therapeutic effect. Further, the role of non-RAI-based modalities, such as secondary extensive metastatectomies with curative intent, external beam radiotherapy, and cytotoxic chemotherapy (mainly with doxorubicin-based regimens) has been unfortunately limited to highly selected cases. Palliative methods for acute clinical management of widely metastatic ThyrCa are also presented, along with anecdotal evidence for the potential therapeutic role for octreotide and its radiolabeled therapeutic peptide analogs, selective estrogen receptor modulators (SERMs), as well as bisphosphonates. Translational bench-to-bedside research has recently led to the identification of the transcriptional machinery as a valid target for future t herapeutic efforts in ThyrCa. Indeed, pre-clinical studies with a variety or agents that affect the rate of thyroid-specific gene transcription, i.e. retinoids, DNA methyltransferase inhibitors, and histone deacetylase inhibitors, have shown their potential for induction of re-differentiation, growth inhibition, promotion of apoptosis and cell cycle regulation. These concerted genomic effects of the above compounds will probably yield novel types of therapies in the clinical arena, especially for RAI-non-avid tumors. Retinoid analogs have already been used in pilot studies in ThyrCa patients with limited success. These re-differentiating agents have raised our expectations for a type of therapy for this malignancy based on a solid molecular rationale, while future progress in the domains of tissue-targeted gene therapy and anti-angiogenesis is eagerly awaited.