Radionuclide imaging is a molecular imaging modality that enables the visualization of physiological, biochemical, and molecular processes within living tissues, primarily through techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). These modalities utilize radiopharmaceuticals to detect functional abnormalities at the cellular and subcellular levels, often before anatomical changes become radiographically evident. The integration of PET or SPECT with anatomical imaging modalities such as computed tomography (CT) or magnetic resonance imaging (MRI) has led to the development of hybrid imaging systems, namely, PET/CT, SPECT/CT, and PET/MRI. These hybrid platforms provide co-registered anatomical and functional data in a single imaging session, enabling precise localization, characterization, and staging of a wide range of oral and maxillofacial pathologies. Hybrid radionuclide imaging achieves its diagnostic capability through the combined use of radiotracers, high-resolution anatomical mapping, and advanced image fusion algorithms. It allows for the simultaneous assessment of structural integrity and biological activity, thereby improving diagnostic accuracy and clinical decision-making in conditions such as head and neck malignancies, inflammatory lesions, salivary gland disorders, and osseous pathologies. This chapter presents a comprehensive overview of the principles, instrumentation, radiopharmaceuticals, imaging protocols, interpretative strategies, clinical indications, and emerging advancements in hybrid radionuclide imaging within the context of oral and maxillofacial radiology.