The tumor microenvironment (TME) is a dynamic network of diverse cellular and noncellular components that interact with malignant cells to influence cancer progression, immune evasion, metastasis, and the development of therapeutic resistance. The major constituents of the TME include malignant cells, immune cells, stromal cells, endothelial cells (ECs), pericytes, adipocytes, nerve cells, and the extracellular matrix (ECM). Findings revealed that a dynamic metabolic crosstalk occurs continuously within the tumor niche, leading to metabolic rewiring in the tumor resident cells that supports cancer progression under nutrient deprivation, hypoxia, and acidosis conditions in TME. This chapter provides a comprehensive overview of various types of metabolic interactions between malignant cells and the diverse cellular components of the TME, including autocrine, paracrine, juxtacrine, and endocrine-like communication, and highlights the role of key metabolites involved in this type of communication. Thus, the interplay between malignant and tumor-resident cells emphasizes their metabolic interactions that promote drug resistance. Additionally, the chapter explores the molecular mechanisms and signaling pathways triggered by this exchange of metabolites. The chapter also explores the molecular mechanisms and signaling pathways triggered by metabolite exchange and clarifies how dysregulated metabolic reprogramming contributes to cancer progression and drug resistance. Therefore, understanding these complex metabolic interactions within the tumor niche provides critical insights for developing novel therapeutic approaches that target the metabolic vulnerabilities of the malignant cells.