The practice of endocrine pathology is undergoing a profound and irreversible revolution, transitioning from a discipline historically reliant on microscopic morphology to an integrated “morpho-molecular” science. The advent, clinical maturation, and widespread adoption of high-throughput sequencing (HTS), colloquially known as next-generation sequencing (NGS), has provided an unprecedentedly deep view into the genomic and transcriptomic landscapes that initiate and drive endocrine neoplasms. This chapter provides a comprehensive, analytical, and in-depth review of the principles and state-of-the-art clinical applications of HTS in the diagnosis, prognostication, and therapeutic management of the major tumors of the endocrine system. A central focus is placed on thyroid carcinoma, which serves as the quintessential model for this new paradigm. We will meticulously explore how molecular testing has become an indispensable, guideline-endorsed tool for resolving diagnostic ambiguity in fine-needle aspiration cytology (FNAC), particularly for the challenging indeterminate nodules (Bethesda categories III and IV), thereby significantly and safely reducing the substantial historical burden of unnecessary diagnostic surgeries. We will dissect the profound prognostic significance of key genetic alterations—including driver mutations in BRAF and RAS, and the critical co-occurrence of TERT promoter mutations—in predicting tumor behavior and refining risk stratification according to the latest clinical guidelines from major international bodies. Furthermore, this chapter details the critical role of HTS in identifying actionable genomic targets, which has paved the way for a new era of personalized, mechanism-based therapies for patients with advanced, metastatic, and refractory endocrine cancers. Beyond the thyroid, we explore the distinct and often uniquely challenging molecular profiles of other endocrine tumors, including pituitary neuroendocrine tumors (PitNETs), where copy-number variations and epigenetic profiling are supplanting mutational analysis as the most informative molecular tools. We also delve into the genetically diverse and complex landscapes of adrenocortical carcinomas and pheochromocytoma/paraganglioma, where germline testing has evolved from a niche consideration to a fundamental cornerstone of patient management and family screening. Finally, we look to the imminent future horizon, discussing the transformative potential of emerging technologies such as single-cell and spatial transcriptomics, the evolving clinical utility of liquid biopsies for noninvasive monitoring, and the integration of artificial intelligence (AI) with digital pathology to synthesize multimodal data, promising an even more precise, predictive, and personalized era of endocrine oncology.