HMGB1 (high mobility group box 1) is released at sites of inflammation and/or tissue damage and promotes cytokine production and cell migration. However, the underlying mechanism for this cell migration is unknown. Now, Schiraldi et al. show that the migration of mouse fibroblasts and human monocytes in response to HMGB1 in vitro depends on CXCL12 and CXCR4. Further analyses showed that HMGB1 forms a heterocomplex with CXCL12 and that this complex triggers different conformational changes in CXCR4 dimers compared with CXCL12 alone. The HMGB1–CXCL12 complex induces the early migration of mononuclear cells into air pouches and to sites of cardiotoxin-induced muscle injury in vivo independently of the HMGB1 receptor RAGE. So, HMGB1 promotes the recruitment of inflammatory cells by forming a complex with CXCL12 that signals through CXCR4.