Bruton’s tyrosine kinase (BTK) is a member of the Tec tyrosine kinase family. 1 BTK is expressed in most hematopoietic cells such as B cells, mast cells, and macrophages but not in T cells, natural killer cells, and plasma cells. 2 BTK plays key roles in multiple cell signaling pathways including BCR and FcR signaling cascades. Mutations in the human BTK gene cause the inherited disease X-linked agammaglobulinemia (XLA), with lack of peripheral B cells and low levels of serum Ig. 3 In XLA, the primary immune deficit is B cell specific. In fact Rituxan, a CD20 antibody, has impacted B cells on the pathogenesis of many autoimmune diseases, such as RA, SLE, and MS. 4 This has fueled interest by multiple pharmaceutical companies in pursuing small molecule BTK inhibitors in the treatment of autoimmune diseases. Likewise, there is also interest in the development of BTK inhibitors for the treatment of hematological malignancies, as aberrant activating BTK has been implicated in the pathogenesis of B cell lymphoma. 5 Detailed reviews and articles on BTK biology and its therapeutic potentials have been reported. 5− 9 Kinase selectivity is a central issue in discovering efficacious and safe small molecule inhibitors for kinase targets, especially for non-life-threatening diseases such as RA. 10 To prevent adverse toxicological events caused by immunological responses, the pharmaceutical industry has largely focused its small molecule drug discovery efforts on agents that interact noncovalently with their target proteins. This strategy has been followed despite numerous examples of marketed drugs with target-specific covalent mode-of-action. 11, 12 In the case of protein kinase targets for which selectivity and efficacy pose major challenges for noncovalent inhibitors, targeted covalent inhibition has provided an attractive alternative. 13 Both approaches, noncovalent and covalent inhibition of protein kinases, benefit tremendously from high resolution structural information from protein crystal structures. This article will review BTK structural biology with a focus on design features for selective BTK inhibitors. We first summarize the publically available structural information on the BTK kinase domain. Then we will provide a brief summary and analysis with key SAR information for the most potent inhibitors reported for the chemical classes that have been disclosed in patents and publications. When available, preclinical and clinical data for advanced compounds will be summarized.