Chronic lymphocytic leukemia (CLL) is a disease of malignant CD5+ B lymphocytes that are characterized by frequent expression of autoreactive B-cell receptors (BCRs) and marked dependence on microenvironmental signals for proliferation and survival. Among the latter, signals propagated through the BCR are believed to play a key role in leukemia initiation, maintenance and evolution. Drugs that can disrupt these signals have recently emerged as potential therapeutic agents in CLL and several of them are currently being evaluated in clinical trials. Particularly promising clinical responses have been obtained with inhibitors of the kinases SYK, BTK, and PI3Kδ, which function by blocking BCR signal transduction. In addition, recent studies focusing on the phosphatase PTPN22, which is involved in the pathogenesis of multiple autoimmune diseases and is markedly overexpressed in CLL cells, suggest that it may be possible in the future to develop strategies that will selectively reprogram BCR survival signals into signals that induce leukemic cell death. This review focuses on the biological basis behind these strategies and highlights some of the most promising BCR-targeting agents in ongoing preclinical and clinical studies.