BTK is a cytoplasmic protein-tyrosine kinase, whose corresponding gene was 
isolated in the early 1990s. BTK was initially identified by positional cloning 
of the gene causing X-linked agammaglobulinemia and independently in a search 
for new kinases. Given the phenotype of affected patients, namely lack of 
B-lymphocytes and plasma cells with the ensuing inability to mount humoral 
immune responses, BTK inhibitors were anticipated to have beneficial effects on 
antibody-mediated pathologies, such as autoimmunity. In contrast to, for 
example, the SRC-family of cytoplasmic kinases, there was no obvious way in 
which structural alterations would yield constitutively active forms of BTK, and 
such mutations were also not found in leukemias or lymphomas. In 2007, the first 
efficient inhibitor, ibrutinib, was reported and soon became approved both in 
the United States and in Europe for the treatment of three B-cell malignancies, 
mantle cell lymphoma, chronic lymphocytic leukemia and Waldenström's 
macroglobulinemia. Over the past few years, additional inhibitors have been 
developed, with acalabrutinib being more selective, and recently demonstrating 
fewer clinical adverse effects. The antitumor mechanism is also not related to 
mutations in BTK. Instead tumor residency in lymphoid organs is inhibited, 
making these drugs highly versatile. BTK is one of the only 10 human kinases 
that carry a cysteine in the adenosine triphosphate-binding cleft. As this 
allows for covalent, irreversible inhibitor binding, it provides these compounds 
with a highly advantageous character. This quality may be crucial and bodes well 
for the future of BTK-modifying medicines, which have been estimated to reach 
annual multi-billion dollar sales in the future.