Learning Objectives: On successful completion of this activity, participants should be able to (1) describe the neural pathways and basic anatomy of the commonly involved cranial nerves with perineural spread of tumor; (2) recognize the imaging findings of perineural spread in head and neck cancers on functional and anatomic imaging; and (3) explain the definition, pathogenesis, and clinical significance of perineural spread. Financial Disclosure: The authors of this article have indicated no relevant relationships that could be perceived as a real or apparent conflict of interest. CME Credit: SNMMI is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing education for physicians. SNMMI designates each JNM continuing education article for a maximum of 2.0 AMA PRA Category 1 Credits. Physicians should claim only credit commensurate with the extent of their participation in the activity. For CE credit, SAM, and other credit types, participants can access this activity through the SNMMI website (http://www.snmmilearningcenter.org) through March 2022. Perineural spread (PNS) refers to tumor growth along large nerves, a macroscopic analog of microscopic perineural invasion. This phenomenon most commonly occurs in the head and neck, but its incidence varies with histologic tumor subtype. PNS results from a complex molecular interplay between tumor cells, nerves, and connective stroma. PNS is clinically underdiagnosed despite its impact on patients' prognosis and management. The role of 18 F-FDG PET in assessment of PNS in head and neck cancer remains to be explored, in contrast to MRI as the established gold standard. In patients with PNS, 18 F-FDG PET shows both abnormality along the course of the involved nerve and muscular changes secondary to denervation. Assessment of PNS on 18 F-FDG PET requires knowledge of relevant neural pathways and can be improved by correlation with anatomic imaging, additional processing of images, and review of clinical context.