Head and neck cancer (HNC) comprises a broad group of malignancies affecting a number of organs in this anatomical region. The most common histologic type is mucosal squamous cell carcinoma of the head and neck (SCCHN). SCCHN accounts for ∼ 50,000 annual cases of HNC in the US. It is an aggressive disease that has been linked to altered growth factor signaling, immune inflammatory responses and angiogenesis. In addition to mucosal SCCHN, increasing frequency of cancer of the thyroid gland has also been recognized over the past several decades. There is a growing interest in the use of biomarker approaches for the early detection of SCCHN and thyroid cancer. This article provides an overview of SCCHN and thyroid cancer and outlines the rationale and need for the clinical application of multiplexed ELISA-based assays as serum proteomic studies for early detection of cancer. Although thyroid cancer has a generally favorable long-term outcome, its screening and diagnosis pose a challenge due to the prevalence of benign nodular thyroid disease, the rising incidence of thyroid cancer, chronicity and recurrence. In the authors' published studies, it was hypothesized that an expanded panel of biomarkers comprised of cytokines, chemokines, growth factors and other tumor markers, which individually may show some promising correlation with disease status, might provide higher diagnostic power if used in combination. The potential clinical role for using these technologies in follow-up, tumor surveillance to permit early identification of recurrence of SCCHN or thyroid cancer in recurrent disease or second primary tumors is discussed.