The mechanism behind mitochondrial abundance in oncocytic (Hurthle cell) lesions is not completely understood; however, it is likely a reflection of excessive mitochondrial proliferation and/or decreased mitochondrial degradation (mitophagy). Such changes are reported to be a result of mutations in the mitochondrial DNA (mtDNA) encoding for mitochondrial enzymes, leading to proliferation through stimulation of transcription factors encoded by the nucleus. Biologically, oncocytic (Hurthle) cells appear to be less active than typical follicular cells, demonstrating lower levels of thyroglobulin production, and oncocytic carcinoma of the thyroid (Hurthle cell carcinoma) have been shown to have markedly lower iodine uptake than their follicular counterparts. Oncocytic thyroid tumors have historically been perceived as carrying a higher risk of malignancy, and in case of malignancy, to carry a worse prognosis than their conventional counterparts. More recent evidence suggests that oncocytic thyroid neoplasms are not more aggressive than usual variants. This chapter discusses the pathogenesis and biological and clinical behavior of oncocytic (Hurthle cell) lesions of the thyroid gland. It also provides a detailed comparison between oncocytic (Hurthle cell) neoplasms and follicular neoplasms.