Here, we review (i) the expression profiles of VEGF, Ang-2, MMP-9, and other factors with potential pro-angiogenic activity in CLL (e.g., FGF-2, TNF-α, CXCL-12, CXCL-2, NGAL, IGF-1, progranulin, and angiogenin), (ii) recent advances in understanding these factors’ respective roles in CLL and their relationship with CLL angiogenesis, and (iii) current strategies for treating CLL, with a focus on the ongoing (pre)clinical development of effective, selective agents intended to target these molecules and block CLL progression. Here, TNF is linked to B-cell chronic lymphocytic leukemia.