Bruton's tyrosine kinase (BTK) is a nonreceptor tyrosine kinase clinically validated to impact B-cell development. Molecules designed to target BTK, through either covalent or reversible inhibition, have transformed the treatment of hematopoietic malignancies. Wen, T.; Wang, J.; Shi, Y.; Qian, H.; Liu, P. Inhibitors targeting Bruton's tyrosine kinase in cancers: drug development advances. Leukemia 2021, 35(2), 312-332.10.1038/s41375-020-01072-6. These advancements are paving the way for new therapeutics to treat nononcology indications, De Bondt, M.; Renders, J.; Struyf, S.; Hellings, N. Inhibitors of Bruton's tyrosine kinase as emerging therapeutic strategy in autoimmune diseases. Autoimmun. Rev. 2024, 23(5), 103532.10.1016/j.autrev.2024.103532 such as multiple sclerosis (MS), and provide benefits to patients with progressive disease. In this context, we describe the discovery of a highly selective, CNS-penetrant, reversible BTK inhibitor designed to sequester Tyr-551, the critical phosphorylation site, into an inactive conformation, thereby blocking B-cell receptor (BCR) signaling. While this class of molecules demonstrated excellent safety when administered at doses that fully inhibited B-cell activity in the periphery, increasing exposure to achieve similar efficacy in the CNS led to adverse findings. This raises the question of whether it was a molecule-specific off-target toxicity or a consequence of blocking BTK function in microglia.