Excluding mycosis fungoides, almost one third of T-cell lymphomas arise as primary tumors in extranodal sites, and these lymphomas are biologically different from their nodal counterparts. The revised European-American classification of lymphoid neoplasms and the World Health Organization classification have emphasized the importance of site in defining T-cell neoplasms and have included such new categories as hepatosplenic gamma delta T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, nasal and nasal-type T-cell lymphoma, enteropathy-type intestinal T-cell lymphoma, and primary cutaneous anaplastic large cell lymphoma. Although site is important, different lymphomas may occur at a particular location, and multiple parameters are required to define each type precisely. Cytologic features usually are not specific, and there are no morphologic correlates, such as follicular nodulation or plasmacytic differentiation in the B-cell system, to help define T-cell neoplasms. The T-cell system is biologically complex, consisting of populations with alpha beta and gamma delta receptors and helper and suppressor/cytotoxic phenotypes. In addition, NK cells resemble T cells in antigen expression, function, and patterns of disease, adding to the difficulty in defining T-cell and NK-cell neoplasms. Therefore, a complete workup with a combination of clinical, immunophenotypic, cytogenetic, and molecular genetic studies often is necessary to characterize these neoplasms. The role of each of these parameters in the diagnosis of T-cell and NK-cell neoplasms is discussed.