The globe is facing a serious concern about skin cancer due to its association with undiagnosed cases in the early stages. This disease developed drug resistance against the conventional medicines and their clinical validations. Hence, there has been an urgent demand for the development of effective therapy for skin diseases. Thus, a detailed understanding of the mechanism of tumor microenvironment (TME) is crucial for the generation of successful therapy. The TME features heterogeneous cellular and structural components, making it difficult to interpret therapy response. During the interaction with surrounding cells, TME causes extensive angiogenesis, remodeling of the matrix, matrix expansion, and fibroblast activation. Further, the immune cells played a critical role in the growth of tumors in TME and also in the modification of the extracellular matrix. So, the new approach for the development of the effective treatment of skin cancer requires targeting the TME and breaking the integration between tumor cells and stroma cells. The associated intracellular signaling in TME and immune cells in response to stimulating tumor growth must be considered. Considering these, the chapter comprehensively highlights the complex role of the microenvironment in tumor cells, the mechanism of TME signaling, and their impact on cancer metastasis.