Chronic lymphocytic leukemia (CLL) is an indolent lymphoproliferative disorder characterized by both circulating peripheral disease as well as involvement of the lymph nodes and bone marrow. Increasing evidence suggests that the stromal microenvironment provides anti-apoptotic and pro-survival signals to CLL cells, and may contribute significantly to resistance to a wide variety of treatments. Our understanding of the complex interactions involved in CLL cell trafficking continues to grow. Chemokines and corresponding chemokine receptors are key factors for organizing CLL cell trafficking and homing and the complex cellular interactions between CLL and accessory cells. Important chemokines include CCL3, CCL4, and CCL22, which are released by CLL cells, and CXCL12, CXCL13, CXCL9, 10, 11, CCL 19, and CCL21, which are constitutively secreted by various stromal cells. Integrins such as VLA-4 (CD49d) as well as selectins and CD44 also likely play a role in directing CLL cell migration within the tissue microenvironments. Data are also emerging that other molecules such as MMP-9 and cytoskeletal proteins also contribute to CLL cell trafficking. Though this interplay is complex, it is critical that we improve our understanding of CLL cell trafficking to facilitate the development of novel therapies that target these pathways. Several drugs in clinical development, such as CXCR4 antagonists and PI3K, Btk, and Syk inhibitors appear to modulate CLL cell trafficking and CLL-stroma interactions. Here, we review the current understanding of the molecular interactions that underlie CLL cell trafficking and we highlight some of the promising approaches underway to target these pathways therapeutically in CLL.