Lung cancer is the main cause of cancer death worldwide, with lung squamous cell carcinoma (LUSC) being the second most frequent subtype. Preclinical LUSC models recapitulating human disease pathogenesis are key for the development of early intervention approaches and improved therapies. Here, we review advances and challenges in the generation of LUSC models, from 2D and 3D cultures, to murine models. We discuss how molecular profiling of premalignant lesions and invasive LUSC has contributed to the refinement of in vitro and in vivo models, and in turn, how these systems have increased our understanding of LUSC biology and therapeutic vulnerabilities.