The current method of cancer management takes into account tumor-related factors to predict therapeutic outcome. However, recent evidence indicates that the host immune system also contributes to therapeutic outcome. Here, we highlight anthracyclines, which have been used to treat a broad range of cancers since the 1960s, as an example of an anticancer treatment that can boost the host's immune system to improve the efficacy of chemotherapy. It has recently been revealed that the translocation of calreticulin to the plasma membrane in tumor cells and the release of high-mobility-group box 1 (HMGB1) by tumor cells are two key post-transcriptional events required for the immunogenicity of anthracyclines. These discoveries represent a conceptual advance in the understanding of the mechanisms underlying the immunogenicity of anthracyclines. We review the effects of anthracyclines on the host immune system and discuss how this knowledge can be exploited for anticancer therapy.