Oral cancer, encompassing malignancies of the oral cavity and oropharynx, stands as a significant global health concern, characterized by its complex etiology and diverse clinical manifestations. Recent advances in cancer therapies have brought hope for improved patient outcomes; however, these breakthroughs have also exposed the intricate web of challenges that surround the management of oral cancer. This chapter offers a comprehensive examination of the multifaceted nature of oral cancer, with an emphasis on the role of cellular and preclinical models in deciphering the intricate molecular mechanisms that drive the disease’s progression and response to treatment. Amid this exploration, we probe the intricate interplay between oral cancer’s heterogeneity and the therapeutic strategies deployed based on the studies made in the genetic and epigenetic makeup of cancer cells. As therapeutic approaches become increasingly personalized, understanding the distinct responses of oral cancer to various treatments within the context of the tumor microenvironment is of paramount importance. Cellular and preclinical models, ranging from in vitro cell cultures to advanced animal studies, illuminate the intricate molecular processes underpinning the disease’s behavior, offering insights that guide the development of more effective therapeutic interventions. This chapter not only serves as a vital resource for researchers, clinicians, and students seeking to navigate the intricate landscape of oral cancer but also highlights the critical need for a deeper understanding of the disease’s complexities to refine treatment strategies and improve patient outcomes. By exploring the multifaceted dynamics of oral cancer and the impact of evolving therapies, we aim to contribute to the ongoing effort to combat this formidable global health challenge.