The proposed model for RhoA/ROCK-dependent cell motility and Rac-dependent proliferation and chemoresistance in CLL. Resting, nonactivated CLL cells arrest in a RhoA/ROCK- and Rac-independent, but CXCL12-mediated, manner to VCAM-1 under shear flow. Furthermore, we observed a Gα_i-, src-, and ROCK-dependent random motility of resting CLL cells on COLL/CXCL12 substrates under shear-free conditions. On their activation by T cells, we noticed a CD40-mediated transcriptional upregulation of Rac1 and Tiam1 in CLL cells, as well as Rac-dependent c-Myc transactivation and cell proliferation. Furthermore, T-cell-mediated CLL cell activation leads to a Rac-dependent resistance toward fludarabine. Dashed lines, an unknown signaling pathway; <mRNA, transcriptional regulation; COLL-R, collagen-receptor; VLA-4, integrin α4/β1 (very late antigen 4); Drug Res., drug resistance; ERM, ezrin/radixin/moesin.