Chemotherapeutic agents have profound effects on cancer, stroma and immune cells that – in most cases – depend upon the dosage and schedule of administration. Preclinical and clinical studies summarized and discussed in the present review have demonstrated that maximum tolerable dosage (MTD) vs low-dosage, continuous (metronomic) administration of most chemotherapeutics have polarized effects on immune cells. In particular, metronomic schedules might be associated – among others effects – with activation of antigen presenting cells and generation of new T cell clones to enhance the activity of several types of immunotherapies. Ongoing and planned clinical trials in different types of cancer will confirm or dismiss this hypothesis and provide candidate biomarker data for the selection of patients who are likely to benefit from these combinatorial strategies. •Metronomic chemotherapy has dose- and schedule-related, distinct effects over cancer, stroma and immune cells.•Combining metronomic chemotherapy with immunotherapy can enhance immune cell modulation for synergistic therapeutic benefits.•Intermittent metronomic chemotherapy activates APCs, generates stem cell-like T cell clones, to enhance the activity of ICIs.•Several clinical trials in different types of cancer are exploring these hypotheses.