Conditioning for allo-HCT causes microbiome-dependent inflammation and can lead to the attack of various organs by donor-derived immune cells (GVHD). Burgos da Silva et al report a number of features of the intestinal microbiome that determine whether GVHD will occur, which organs are affected (the most severe form is GVHD of the lower gastrointestinal tract, LGI-GVHD), and that affect disease outcome. Professional illustration by Patrick Lane, ScEYEnce Studios.