Approximately 80% of patients with advanced prostate cancer (PCa) have bone metastases, and virtually all of these men succumb to their disease. It is now well established that the interactions between the TME (fibroblasts, endothelial cells, osteoblasts, osteoclasts and immune cells) and cancer epithelial cells in the bone are critical in metastatic progression. Cancer- and TME-derived extracellular vesicles, enriched in DNA, coding/non-coding RNA and proteins, are key mediators of such intercellular communication between cancer cells and the TME (stroma cells and immune effectors). We have performed molecular profiling of cancer and stroma derived extracellular vesicles from patients who are undergoing therapies for bone metastases. The molecular profiles of exosomes provided us with important insights into i) the role of local and systemic therapy in PCa progression; ii) the differential expression profiles of TME-targeting agents in patients who benefit or not benefit from the treatments; iii) mechanisms of resistance to TME-targeting therapies; and iv) potential combination therapies that may overcome these therapeutic challenges.