Human skin is one of the largest organs in the body, making it highly susceptible to harmful factors, including ultraviolet radiation, which is the primary cause of skin malignancies. Skin cancers, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and cutaneous melanoma, represent significant global health concerns. This chapter focuses on novel approaches to the development and application of advanced skin cancer models in research. To begin, an overview of the skin structure is provided, followed by a detailed discussion of skin cancer types and their key characteristics, along with statistics on their incidence and mortality according to GLOBOCAN database. Current treatment options for these malignancies are also compared based on the Food and Drug Administration—Approved Drug Library, highlighting the need for more effective therapies. Next, the transition from the two-dimensional (2D) to three-dimensional (3D) cell culture methods is introduced, with a PubMed database meta-analysis and a description of the reagents, and techniques used to establish advanced skin (cancer) models such as spheres/spheroids or equivalents. Finally, examples of methods employed for the analysis of these skin cancer models, including various microscopy techniques, transcriptomic and proteomic analyses, and other cutting-edge analytical approaches, are considered. This chapter underscores the importance of 3D models in enhancing the understanding of skin cancer biology and facilitating the development of improved therapeutic strategies.