Metronomic chemotherapy involves the administration of cytotoxic chemotherapy at reduced doses administered at regular and frequent intervals. Low-dose metronomic (LDM) chemotherapy represents an alternative to standard maximum tolerated dose (MTD) chemotherapy as it is less toxic and offers additional beneficial biological effects; such effects include inhibition of tumor neovascularization and reduced recruitment of immune-suppressive cells. In desmoplastic cancers such as breast and pancreatic cancers, carcinoma-associated fibroblasts (CAFs) in the tumor stroma constitute an important cellular target of systemic chemotherapy, and the treatment-modulated CAFs may deleteriously influence treatment efficacy. Herein, we reviewed the novel roles of CAFs in metronomic chemotherapy in desmoplastic cancers. We discuss the differential effects of MTD- and LDM-chemotherapy on the heterotypic interactions among CAFs and cells in the other cancer compartments, emphasizing the roles of cancer stem cells and myeloid-derived suppressor cells. The novel mechanistic roles of CAFs in cancer therapy provide an additional rationale for the clinical development of LDM chemotherapy.