Lymphocyte adhesion to high endothelial venules, a central step during extravasation into lymphoid tissues, involves an 85 to 95-kD class of lymphocyte surface glycoproteins, which fall in the cluster of CD44 antigens. In this paper we describe the expression of this homing receptor glycoprotein during lymphoid development. CD44 expression was examined on a large panel of non-Hodgkin's lymphomas (n = 234) and lymphoid leukemias (n = 44). These tumors, which are the malignant counterparts of normal lymphoid cells "frozen" at a certain stage of maturation/activation, are thought to represent a complete spectrum of lymphoid development from stem cell to mature, activated T and B lymphocyte. It was found that CD44 exhibits a trimodal distribution on developing lymphocytes of both the T and B lineage: the CD44 antigen is expressed at relatively high levels during early stages of lymphoid differentiation, i.e., on prothymocytes and immature precursor B cells (null acute lymphoblastic leukemia (ALL) and common ALL). Subsequently, at the stage of the immature/common thymocyte, the pre-B cell and early B cell (pre-B-ALL and B-ALL), the CD44 antigen is temporarily lost from the cell surface to be reacquired during further T and B cell maturation. At the activated (germinal center) B cell stage. CD44 is heterogeneously expressed. This distribution pattern of the CD44 molecule closely matches the recirculatory versus sessile nature of lymphoid cells at consecutive phases of their development, and thus apparently reflects its homing receptor function. In addition, the relatively high expression of the CD44 antigen in the earliest phases of T and B cell development suggests that the molecule may also be involved in the migration of bone marrow derived lymphoid precursors to their site of maturation.