Head and neck/oral cancer (HNOC) is a devastating disease. Despite advances in diagnosis and treatment, mortality rates have not improved significantly over the past three decades. Improvement in patient survival requires a better understanding of the disease progression so that HNOC can be detected early in the disease process and targeted therapeutic interventions can be deployed. Accumulating evidence suggests that microRNAs play important roles in many human cancers. They are pivotal regulators of diverse cellular processes including proliferation, differentiation, apoptosis, survival, motility, and morphogenesis. MicroRNA expression patterns may become powerful biomarkers for diagnosis and prognosis of HNOC. In addition, microRNA therapy could be a novel strategy for HNOC prevention and therapeutics. Recent advances in microRNA expression profiling have led to a better understanding of the cancer pathogenesis. In this review, we will survey recent technological advances in microRNA profiling and their applications in defining microRNA markers/targets for cancer prediction, diagnostics, treatment, and prognostics. MicroRNA alterations that consistently identified in HNOC will be discussed, such as upregulation of miR-21, miR-31, miR-155, and downregulation of miR-26b, miR-107, miR-133b, miR-138, and miR-139.