OSCC is the most frequent malignant tumour of the oral cavity, accounting for more than 90% of malignant tumours of this anatomic region and it often arises from precursor lesions. Aside from tobacco and alcohol consumption, further determinants have been considered to increase the risk of OSCC development, such as micronutrient deficiencies, chronic traumatism, poor oral hygiene and viruses. Recurrence, survival and conversely, mortality depends on numerous and different biological, histological, macroscopic and microscopic factors that have been investigated in order to define causes, to help diagnosis and to refine appropriate treatments that perfectly fit with the different features of OSCCs. For this purpose, during the last decades, the improvement of scientific technologies and molecular analyses have allowed to investigate markers and genetic and epigenetic factors, in order to clarify their responsibilities related to early diagnosis and OSCC progression and prognosis in order to address them as targets in future selective and individually-shaped therapies. This review will focus on the etiology, advances in diagnostic markers and prognostic indicators for oral cancers.