The tumor microenvironment (TME) orchestrates cancer progression by fostering a complex interplay between cancer cells and the surrounding cellular and acellular elements. Through dynamic interactions with cancer cells, vascular and stromal cells not only promote tumor growth but also enhance metastatic potential and restrict therapeutic responses. Vascular and stromal cells play a critical role in regulating epithelial-mesenchymal transition (EMT) and sustaining resistance pathways, making them compelling targets for innovative therapies. This review delves into the vascular and stromal components of the TME, their contributions to EMT and resistance mechanisms, and emerging strategies to target these interactions for improved cancer therapy outcomes.