Chronic lymphocytic leukemia (CLL) remains associated with low complete response rates and high relapse rates. This is in part due to poor understanding of CLL biology and thus inadequate targeting of therapy. For years CLL has been proposed as bi-compartmental: the quiescent tumor in the periphery and the proliferating cells within specific microenvironments. Historically the bone marrow was considered the major tissue of the CLL microenvironment. However, many recent innovative studies have categorically shown that peripheral CLL cells are derived from the lymph nodes (LN). Proliferation here is largely driven by helper T cells via CD40-CD40L engagement. Critically, in vitro studies have shown that such engagement additionally protects LN CLLs from apoptosis. Agents inducing apoptosis in non-CD40 engaged CLL cells are frequently ineffective against those continually engaged with CD40L. This emphasizes that, in order to improve responses and prevent relapse, novel therapies must be assessed against CD40L engaged CLL cells to show effective targeting against the LN. This review discusses the evidence supporting the superior involvement of the LN in CLL, how CD40L engaged CLL studies should be conducted, and the novel therapies studied in vitro and in vivo that have been proposed to be effective in this setting.