Background: Head and neck squamous cell carcinomas (HNSCCs) are particularly aggressive epithelial tumors, that affect more than half a million patients worldwide each year. They represent a multi-factorial group of tumors caused by: alcohol, tobacco, and human papillomavirus (HPV) infections. Over the last ten years the overall 5-year survival rate of HNSCCs remained ~40–50%, inspite of significant improvement in clinical outcome of many tumor types. There are recent data that claim how some of these cells fulfill a suppressive role in the antitumor immune response. It is interesting that new clinical studies demonstrated that HPV (+) HNSCCs were among tumors with the highest immune infiltrates, while HPV (-) presented a reduced number of immune infiltrating cells. Conclusions: Recent researches prove that tumor microenvironment of HNSCC has an important role in tumor progression, aggressivity, metastasis process, in addition to genetic aberrations and molecular alterations of cancer cells. New researches in stromal composition of the HNSCC may be useful in understanding of mechanisms of different responses to therapy, also can be used as a target for therapeutic purposes. Cancer-associated fibroblasts and immune cells, as well as their products found in neck squamous cell carcinoma significantly influence the biological properties of this tumor. Smoking is one of the risk factors of occurrence of most HPV-associated tumors. Promoting smoking cessation should become an essential contributor to the treatment of cancer in all oncologic pathologies. In cases when patients can’t quit smoking completely within the shortest possible period of time, doctors should focus on harm reduction strategies – tobacco harm reduction.