On the basis of the experience derived from the study of 2,000 biopsies, the authors critically review the problem of the newly generated monoclonal antibodies (mAbs) working in paraffin sections. The reliability and drawbacks of the most commonly used reagents are examined, with special reference to their employment in the diagnosis of malignant lymphomas. The authors underline that only a few mAbs are really specific, since most reagents give rise to a certain number of cross-reactivities. In the light of this, a wide panel of antibodies should always be applied in the diagnosis of lymphoid tumors in order to avoid possible misinterpretations, which can actually lead to wrong therapeutical decisions.