The tumor-stroma interaction is critical for the development and progression of cancer. Cancer-associated fibroblasts (CAFs), one of the major components of the tumor stroma, can promote tumor growth and metastasis. Exosomes are secreted microvesicles that mediate cell-to-cell communication. Exosomal contents, including proteins, nucleic acids, and lipids, can be shuttled from donor cells to target cells. Recent studies suggest that exosomes play important roles in the tumor-stroma interaction. Herein, we review the multifaceted roles of exosomes in the tumor-stroma interaction and the underlying molecular mechanisms. Literature search for all relevant publications was performed on PubMed databases. The keywords of exosomes, tumor, stroma, CAFs, mesenchymal stem cells (MSCs) and other closely related terms were used for searching. Tumor cell-derived exosomes induce the differentiation of fibroblasts and MSCs into CAFs. In turn, exosomes secreted by CAFs promote tumor growth, metastasis, and drug resistance through distinct mechanisms. Moreover, exosomes from stromal cells can be used as therapeutic vehicles for the delivery of anticancer drugs. Tumor cells communicate with CAFs through exosomes, which establishes a bidirectional cross talk to promote tumor growth, metastasis, and drug resistance. Targeting exosomes in tumor-stroma interaction may have important implications for anticancer therapy.