Accumulating evidence indicates that expression of anaplastic lymphoma kinase (ALK), typically due to t(2;5) translocation that creates an NPM-ALK fusion gene, defines a distinct type of T/null-cell lymphoma (TCL) within a vastly heterogeneous group of anaplastic large cell lymphomas. Through the translocation mechanism or as a full-length apparently intact protein, ALK also is expressed by a subset of inflammatory myofibroblastic tumors, glioblastomas, diffuse large B-cell lymphomas, and other malignant neoplasms. Owing to the recent progress in understanding its pathogenesis, ALK+ TCL has become a model malignant neoplasm in which morphology-based diagnosis and classification are gradually shifting toward biology-based diagnosis. Several lines of experimental evidence indicate that the ectopically expressed ALK is oncogenic in ALK+ TCL by being constitutively active owing to autophosphorylation and, consequently, by stimulating several critical signal transduction pathways involving phospholipase C-gamma, AKT, and STAT3 (signal transducer and activator of transcription 3). Targeting ALK and, perhaps, its downstream signaling effector proteins represents a promising novel therapeutic approach to ALK+ TCL. Diagnostic implications of the ALK expression in ALK+ TCL and other malignant neoplasms and the related current controversies are discussed.