The endogenous TLR9 signaling supports CLL cell migration, homing to lymphoid organs and progression. Cell-free and mitochondrial DNA, with unmethylated cytosine-phosphate-guanosine motifs, triggers activity of TLR9 in CLL cells. TLR9 activation stimulates NF-κB and STAT3 signaling, which synergize with BTK to promote CLL cell migration and homing into lymphoid organs.