A detailed analysis of the role of determinant presentation in the process of triggering immunocompetent lymphocytes has been made utilizing cell-bound hapten-carrier conjugates to elicit secondary antihapten antibody responses, primarily in vitro. The results of these experiments demonstrate that: (a) hapten-protein conjugates will attach to the surface membranes of macrophages directly, in the absence of specific antibodies, in a highly immunogenic form; (b) such macrophage-bound conjugates serve as remarkedly efficient stimuli to trigger both thymus-derived (T) and bone marrow-derived (B) cells in a specific manner, lowering the optimal threshold antigen dose (in molar terms) by several logs as compared with soluble antigen; (c) the macrophage is not unique in this regard, since fibroblasts are essentially comparable in the capacity to present antigen in highly immunogenic form; (d) cell surface-bound antigen clearly favors secondary in vitro responses of the IgG as compared with the IgM antibody class; (e) in terms of triggering B or T cells, antigen bound to macrophages in the form of immune complexes does not appear to possess any appreciable advantage over equimolar quantities of directly attached antigen; (f) the increased immunogenicity of cell-bound antigen appears to reflect certain crucial, and undefined, features of cell surface membranes and not merely the stabilization of determinants on a relatively immobile surface; and (g) although the efficiency of lymphocyte triggering is markedly enhanced by cell-bound antigen, the presence of macrophages is apparently not an absolute requirement for eliciting secondary in vitro antibody responses to soluble hapten-protein conjugates. The relevance of these observations to the nature of the signal induced upon antigen interaction by specific lymphocytes and the sequential cellular events involved in the regulatory influence of activated T cells on B cell responses to antigen is discussed. We postulate that T lymphocytes are best triggered by cell-bound antigen and that after this step the activated T lymphocytes regulate the triggering of B cells with antigen.