In 2022, the new WHO Classification of Endocrine and Neuroendocrine Tumors, Fifth Edition was published. Large-scale genomic analyses such as The Cancer Genome Atlas (TCGA) have revealed the importance of understanding the molecular genetics of thyroid tumors. Genetic mutations in follicular cell–derived neoplasms highlight the role of mutations in the MAP kinase pathway, including RET, RAS, and BRAF, as drivers of carcinogenesis. The genetic profile of oncocytic carcinoma of the thyroid (Hurthle cell carcinoma—HCC) differs from that of papillary thyroid carcinoma and follicular thyroid carcinoma. Molecular pathways that differentiate oncocytic adenoma (Hurthle cell adenoma—HCA) from widely invasive HCC (wiHCC) include the PIK3CA-Akt-mTOR and Wnt β-catenin pathways, providing rationale toward new targets of this type of malignancy in the future. Despite having a common origin in the follicular cell, follicular thyroid carcinoma and oncocytic/HCC should be considered as two separate entities due to the significant difference in oncogene expression between both. Changes in both nuclear DNA and mitochondrial DNA (mtDNA) suggest the diagnosis of oncocytic/HCC. Molecular changes in nuclear DNA involve several signaling pathways and mitochondrial functions. Mitochondrial genetic changes involve interaction between mutations in the mitochondrial and nuclear genomes. This chapter discusses the updates in molecular and genetic diagnostics of oncocytic/Hurthle cell carcinoma. The WHO fifth edition (2022) emphasizes the importance of classifying tumors based on both genetic abnormalities and histomorphology. This approach aids in achieving accurate pathological diagnosis and facilitates the early selection of appropriate treatment options, including molecular targeted therapies.