Staphylococcal protein A (SpA) protects Staphylococcus aureus from antibody binding. Furthermore, SpA can crosslink B cell receptors and thus modulate B cell function. However, it has been unclear how SpA reaches B cells, as it is anchored to the staphylococcal cell wall. Missiakas and colleagues now show that SpA, together with part of its peptidoglycan anchor, is cleaved off the cell wall by the bacterial murein hydrolases LytN and LytM and is released into the extracellular milieu. LytN alters the peptidoglycan anchor of SpA by removing amino sugars, and LytM then cleaves the remaining pentaglycyl cross-bridge that attaches the anchor to the cell wall. Importantly, the amino sugars (MurNAc–GlcNAc) that are removed by LytN are potent immunostimulators. Thus, the released and modified form of SpA can target B cells without triggering innate immunity.