An integrative histologic and molecular classification of thyroid tumors has become clinically relevant due to the potential role in risk stratification and selection of targeted therapy. In this review, we discuss the applications of six "next-generation" immunohistochemical markers, namely BRAF V600E (clone VE1), RAS Q61R (clone SP174), pan-TRK (clone EPR 17341), ALK (clones 5A4 or D5F3), PTEN, and β-catenin in the pathologic diagnosis and molecular classification of thyroid tumors. These biomarkers allow the in situ examination of tumor tissue and assist in the diagnosis and pathologic staging by highlighting tumor border and patterns of invasion, identifying isolated tumor cells in lymph nodes, distinguishing lymph node metastasis from benign intranodal thyroid inclusions, and diagnosing multicentric thyroid carcinomas with discordant molecular drivers. Furthermore, it can identify specific thyroid neoplasms that may occur sporadically or may be associated with hereditary syndromes. The next-generation immunohistochemistry provides a novel solution to challenging issues in thyroid pathology and fast turn-around time for accurate molecular classification and further guidance of therapeutic management.