Targeted therapy with imatinib and other selective tyrosine kinase inhibitors has transformed the treatment of chronic myeloid leukemia. Unlike chronic myeloid leukemia, chronic lymphocytic leukemia (CLL) lacks a common genetic aberration amenable to therapeutic targeting. However, our understanding of normal B-cell versus CLL biology points to differences in properties of B-cell receptor (BCR) signaling that may be amenable to selective therapeutic targeting. The application of mouse models has further expanded this understanding and provides information about targets in the BCR signaling pathway that may have other important functions in cell development or long-term health. In addition, overexpression or knockout of selected targets offers the potential to validate targets genetically using new mouse models of CLL. The initial success of BCR-targeted therapies has promoted much excitement in the field of CLL. At the present time, GS-1101, which reversibly inhibits PI3Kδ, and ibrutinib (PCI-32765), an irreversible inhibitor of Bruton tyrosine kinase, have generated the most promising early results in clinical trials including predominately refractory CLL where durable disease control has been observed. This review provides a summary of BCR signaling, tools for studying this pathway relevant to drug development in CLL, and early progress made with therapeutics targeting BCR-related kinases.