An escalation in the incidence of oral cancer and its attributable mortality has been observed in recent decades in Europe; oral cancer is expected to become a public health problem in the foreseeable future. However, survival rates have remained at a disappointingly stable level despite significant development in the multimodality treatment of the disease. Additionally, due to the limited prognostic value of conventional prognostic factors and the uniformity of treatment strategies, several patients are still over- or under-treated with significant personal and socio-economical impact. Here we review some promising prognostic and predictive markers that can help the clinician to improve prognostic accuracy and define the most appropriate management for the individual patient with oral cancer.