Squamous cell carcinoma (SCC) is by far the most common malignancy of the upper aerodigestive tract. Most conventional-type SCCs do not present the surgical pathologist with diagnostic difficulty. Certain variants, however, can histologically mimic benign and other malignant diseases. In such cases, correct diagnosis is important for prognostic and therapeutic reasons. This article discusses the clinicopathologic features of the upper aerodigestive tract variants of SCC, including verrucous carcinoma, papillary squamous cell carcinoma, basaloid squamous cell carcinoma, spindle cell carcinoma, adenosquamous carcinoma, adenoid squamous cell carcinoma, and undifferentiated carcinoma. It also discusses the differential diagnoses that must be considered and the use of ancillary testing, especially immunohistochemical analysis, for determining the correct diagnosis.