Last decade major advances have been made in the field of mouse model engineering. Newly developed conditional mouse models have overcome important drawbacks in conventional mouse models. Conditional mouse models are especially suited for the development of models of sporadic human carcinomas. These models can control gene (in)activation in a time and/or tissue-specific manner. Here, we review two important conditional mouse model systems, based on the Tet off/on and the Cre-Lox system. Furthermore possible applications of the Cre-Lox system in the development of a mouse model for HNSCC are being discussed. In the future, conditional mouse models for HNSCC can be used in the identification of new key genes in HNSCC tumorigenesis, and would furthermore serve as an indispensable tool for designing new treatment-modalities.