This review encompasses the most salient advances in the understanding of the biopathology of head and neck squamous-cell carcinoma (HNSCC) accomplished over the last decade, emphasizing the significant role played by high-risk HPV genotypes. This has led to a new and meaningful subdivision of conventional HNSCC in two main prognostic and therapeutic groups: 1) keratinizing HNSCC, mainly occurring in elderly men that are heavy smokers and drinkers, TP53 mutated and/or p53-positive, HPV16-negative, being associated with an aggressive course; and 2) non-keratinizing HNSCC, occurring in younger men between 40 and 60 years that are non-smokers and non-drinkers, HPV16- positive, p16-positive, and p53- negative, being associated with improved prognosis. The main risk factors are number of sexual partners, oral-genital sex, oral-anal sex, and marijuana use. Among the unusual variants of HNSCC, papillary and lymphoepithelial-like are mostly related to HPV-16 infection, whereas the spindle and acantholytic types are mainly associated with tobacco and alcohol. The basaloid, adenosquamous, and verrucous variants may be related to both types of risk factors. Spindle cell carcinoma has been shown to be a prototype of epithelial mesenchymal transition. The hallmark of the novel and aggressive entity "undifferentiated midline carcinoma" is the rearrangement of the Nuclear Protein in Testis (NUT) gene at t[15; 19]. In the HPV era we are proposing the Ljubljana Classification (LC) as the recommended system for grading precursor lesions in heavy cigarette smokers and alcohol drinkers and the dysplasia and SIN systems for grading intraepithelial precursor lesions related to the increasingly detected epidemic of HNSCC associated with high-risk HPV infections.