Tyrosine kinases play a fundamental role in cell proliferation, survival, adhesion, and motility and have also been shown to mediate malignant cell transformation. Here we describe constitutive expression of the protein tyrosine kinase Brk in a large proportion of cutaneous T-cell lymphomas and other transformed T- and B-cell populations. The kinase is expressed in the nuclear localization and activated state. Brk expression was also induced in normal T cells on their activation. Introduced expression of the Brk gene resulted in markedly diminished cytokine and growth factor dependence of transfected BaF3 lymphocytes in regard to their in vitro proliferation and survival. Brk also conferred in vivo oncogenicity on the BaF3 cells. siRNA-mediated inhibition of the endogenous Brk in malignant T cells diminished their growth and survival capacity. These findings document inducible expression of Brk in normal T lymphocytes and persistent expression of the activated kinase in malignant T and B cells. Furthermore, our results indicate that Brk may play a key role in lymphomagenesis, hence identifying the kinase as a potential therapeutic target in lymphomas.