Although conventional squamous carcinomas can often be recognized with little difficulty by experienced pathologists, it remains a fact that a substantial number of head and neck malignancies are capable of posing real challenges to the diagnostic pathologist. Those head and neck tumors showing the least kinship with normal host tissues-that is, the undifferentiated malignancies-are a particular problem and an approach to dealing with them is traced out below. As a matter of basic light microscopy, these tumors can usually be relegated to 1 of 4 categories: small round cell tumors, spindle cell tumors, large polygonal cell (epithelioid) tumors, and pleomorphic tumors. Once they have been so subclassified, these lesions can then be studied by immunohistochemistry and, when necessary, by molecular methods as well. Immunohistochemistry often permits these tumors to be assigned to a particular tissue type, specifically, epithelial, mesenchymal, lymphoid, or melanocytic. Application of additional immunohistochemical antibodies, in turn, can permit further refinement of this impression (eg, allowing distinction of a neuroendocrine tumor from a carcinoma). In selected instances, molecular techniques (such as in situ hybridization) may be employed both for diagnostic as well as for prognostic purposes. It should be borne in mind, however, that the pathologist's diagnosis will sometimes only be as good as the clinical information provided, which is why the diagnosis of undifferentiated malignancies of the head and neck truly is a multifaceted process, demanding the close cooperation of pathologists, clinicians, and radiologists.