Certain tumors of the head and neck use peripheral nerves as a direct conduit for tumor growth away from the primary site by a process known as perineural spread. Perineural spread is associated with decreased survival and a higher risk of local recurrence and metastasis. Radiologists play an important role in the assessment and management of head and neck cancer, and positron emission tomography/computed tomography (PET/CT) with 2-[fluorine 18]fluoro-2-deoxy-d-glucose (FDG) is part of the work-up and follow-up of many affected patients. Awareness of abnormal FDG uptake patterns within the head and neck is fundamental for diagnosing perineural spread. The cranial nerves most commonly affected by perineural spread are the trigeminal and facial nerves. Risk of perineural spread increases with a midface location of the tumor, male gender, increasing tumor size, recurrence after treatment, and poor histologic differentiation. Focal or linear increased FDG uptake along the V2 division of the trigeminal nerve or along the medial surface of the mandible, or asymmetric activity in the masticator space, foramen ovale, or Meckel cave should raise suspicion for perineural spread. If FDG PET/CT findings suggest perineural spread, the radiologist should look at available results of other imaging studies, especially magnetic resonance imaging, to confirm the diagnosis. Knowledge of common FDG PET/CT patterns of neoplastic involvement along the cranial nerves and potential diagnostic pitfalls is of the utmost importance for adequate staging and treatment planning.