BTK is a kinase that functions downstream of multiple receptors in various hematologic cells. This review focuses on BTK-dependent pathways that are likely to be involved in maintaining the malignant phenotype in B-cell lymphomas and leukemias. Survival of various B-cell malignancies requires BTK-dependent signals from the B-cell antigen receptor. Survival is also dependent on malignant cells homing to and interacting with lymphoid microenvironments, and these interactions are also BTK-dependent due its role in signaling downstream of chemokine and innate immune receptors. The potential for therapeutic targeting of BTK is currently being tested in clinical settings.