While the implementation of multi-modality neoadjuvant therapy for the treatment of head and neck cancer has resulted in an improvement in local regional control, there has been a resultant increase in the reported incidence of distant metastasis. This shift in the pattern of patient treatment failure highlights the importance of identifying patients at high risk of developing metastasis, accurately detecting metastasis, and improving treatment strategies for advanced disease. Currently, metastatic lesions from head and neck primaries portend a poor prognosis; however, molecular biologic techniques offer a promising approach to the diagnosis and treatment of micrometastasis and distant metastatic lesions. The identification of tumor-specific gene mutations and the cell surface antigens may play a key role in the future management of head and neck cancer. The following review outlines just several of the current issues related to the contemporary diagnosis and management of metastatic lesions of the head and neck.