Introduction Global analysis methods (genomics, transcriptomics and proteomics) have marked the last decade, trying to identify new factors involved in malignant cell transformation. Aim A proteomic profiling of oral mucosa tissue of patients with potentially malignant (oral lichen planus) or malignant oral lesions (squamous cell carcinoma) and patients without oral changes has been conducted to explore new potential biomarkers which would enhance making of an early diagnosis and treatment of potentially malignant and malignant lesions. Materials and methods Proteomic analysis of these lesions was made using mass spectrometry, and some markers identified by mass spectrometry were validated by Western blotting. Furthermore, since insulin-like growth factors and their receptors are thought to play an important role in the growth of normal somatic cells, the expression status of the insulin-like growth factor 2 and its receptor, IGF2/IGF2R, have been explored in the same type of lesions and also in specimens of oral leukoplakia, using immunohistochemistry. Results and conclusion The analysis of differentially expressed proteins in changed tissues compared to control tissues (oral mucosa without changes of the same patient and healthy tissue) pointed to a crucial role of extracellular matrix proteins in development of oral lesions, especially an important role for lumican in oral cancer. Most of the differentially expressed proteins in altered mucosa of patients with oral lichen planus have been included in cytoskeletal changes, keratinization, morphogenesis and cell signaling. Immunohistochemical analysis of IGF2 and IGF2R expression has determined a significant difference in expression percentage of IGF2 and the expression intensity of IGF2R in a population of healthy patients compared to the patients with lesions of oral lichen planus, leukoplakia and head and neck carcinoma.