Clinical evaluation of head and neck cancer patients requires eliciting a complete history and a physical examination requiring a thorough assessment of the tumor, the patient and the social milieu in which the patient lives. The clinician is expected to establish a preliminary diagnosis, develop a relationship of trust with the patient and family members, initiate additional diagnostic investigations, formulate a treatment plan and coordinate patient care with a multidisciplinary team. This chapter will address the anatomy of the oral cavity and oropharynx as well as the required components of initial in-office assessment of the patient and the key differential diagnoses to consider.