The experimental findings of Laouedj et al illustrated here include (1) autocrine production of S100A8/A9 proteins by AML cells; (2) induction of differentiation through S100A9-dependent TLR4 activation in AML4/5 subtypes; (3) therapeutic potential of S100A8 blocking and/or S100A9 activation in murine models. (4) Beyond these findings, we hypothesize that targeting S100A8/A9 proteins may synergize with chemotherapy, as observed in acute APL treated with chemotherapy and differentiating agents. (5) Given that S100 proteins have recognized effects against the reduction of antitumor immunity by tumor microenvironment cells, S100A8/A9-targeted therapies may also enhance AML immune response and therefore synergize with novel immunotherapeutic modalities. Professional illustration by Patrick Lane, ScEYEnce Studios.