Head and neck squamous cell carcinomas (HNSCC) are among the leading causes of cancer related deaths throughout the world. The survival rate for this type of cancer is extremely low and has not changed significantly in recent decades. There is an imperative need to study tumor progression in a representative model in order to generate more knowledge about this disease as well as develop more effective treatment options. Multiple methods already exist for studying HNSCC and other types of cancers, including in vitro and in vivo models. Although in vivo models are more representative of the human carcinomas in terms of complexity of the microenvironment the tumor cells experience, they are difficult to manipulate and many experiments cannot be performed easily in whole organisms; therefore, in vitro models are used. Current in vitro models are typically two-dimensional (2D) monolayer cultures that are easily manipulated for a controlled environment, but these fail to mimic the native microenvironment in terms of three-dimensional (3D) interactions present in vivo. The literature documents that several 3D organotypic models of HNSCC have been created, showing significant differences in tumor response to drugs between these models and traditional 2D culture systems, perhaps suggesting a closer representation of human HNSCC. However, these models were not rigorously validated, with little comparison to in vivo tumor behavior. We developed a 3D HNSCC in vitro model using electrospun scaffolds to mimic the extracellular matrix as well as using a HNSCC-derived tumor cell line, HN12, in co-culture with a supporting fibroblast cell line. We compared the model to the same tumor cell line grown in vivo in immunodeficient mice. We also investigated drug sensitivity of tumor cells in our model compared to conventional monocultures to determine whether differences exist. Finally, we investigated pro-angiogenic properties of tumor cells in this model. The long-term goal is to develop a model that can be manipulated easily to study tumorigenic mechanisms and potential treatments.