Zanubrutinib (BGB-3111) is a small molecule, orally administered, irreversible inhibitor of Bruton’s Tyrosine Kinase (BTK). Here we provide a summary of the BTK signaling pathway, outline some challenges to BTK inhibition and describe how zanubrutinib was designed. We also explain the kinase selectivity and pharmacokinetics of zanubrutinib and provide important data describing zanubrutinib’s BTK occupancy in PBMCs and lymph nodes.