The epidermal growth factor receptor- (EGFR-) directed antibody, cetuximab, was FDA-approved for the treatment of squamous cell carcinoma of the head and neck (SCCHN) in 2006. Additional EGFR-targeting agents in clinical development for SCCHN include other EGFR-directed antibodies, tyrosine kinase inhibitors and antisense DNA. Although the majority of SCCHN overexpress EGFR, SCCHN clinical responses to EGFR-targeting agents have been modest. Molecular predictors for SCCHN response to EGFR-targeted therapies have not been identified. However, molecular correlate studies in lung cancer and colon cancer, which have EGFR-targeted therapeutics FDA-approved for treatment, may provide insights. We describe candidate predictive markers for SCCHN response to EGFR-targeted therapies and their prevalence in SCCHN. Clinical response will likely be improved by targeted therapy combination treatments. Src family kinases mediate EGFR-dependent and -independent tumor progression pathways in many cancers including SCCHN. Several Src-targeting agents are in clinical development for solid malignancies. Molecular correlate studies for Src-targeting therapies are few and biomarkers correlated with patient response are limited. Identifying SCCHN patients who will respond to combined EGFR- and Src-targeting will require further characterization of molecular correlates. We discuss rationale for EGFR and Src co-targeting for SCCHN treatment and describe recent clinical trials implementing combined Src- and EGFR-targeted therapeutics.