Chronic Lymphocytic Leukemia (CLL) B cells display characteristics consistent with a defect in programmed cell death (apoptosis) and exhibit prolonged survival in vivo. When recovered from peripheral blood or lymphoid tissues from the patient and cultured in vitro, these malignant cells rapidly undergo spontaneous apoptosis. This observation suggests that the selective survival advantage enjoyed by CLL B-cells is not entirely autonomous, raising the possibility of manipulating CLL B-cell survival by iatrogenic means. The extended survival of the neoplastic B-cells creates a permissive soil on which oncogene activation, genetic instability and accumulation of gene mutations favoring disease progression can occur. In addition, such survival-promoting microenvironments can rescue leukemia cells from cytotoxic therapy, giving way to disease relapse. Survival of CLL B-cells is influenced by interactions with non-leukemia cells in the microenvironment of lymph nodes, marrow and other tissues. CLL B-cells have developed many different ways to escape undergoing apoptosis. These include: (a) expression of survival receptor as well as their ligands, giving rise to autocrine survival pathways which are leukemia cell specific; (b) defects in plasma membrane receptor cell signaling, triggered by death receptors such as Fas- and TRAIL; and (c) constitutively active survival signaling pathways such as NFkappaB and PI3K/Akt. Here we discuss some of the molecular mechanisms by which interaction with other cells and factors in the microenvironment provides survival advantages to CLL B-cells in specific in vivo niches, and we suggest some strategies for overcoming these anti-apoptotic mechanisms for improving treatment of CLL.