The activation of B lymphocytes from the resting stage to the proliferating stage and then to the fully differentiated antibody-secreting stage is a highly regulated and complicated process. B-cell activation can clearly proceed by a number of different routes, each promoted by different regulatory cells (macrophages, two types of helper T cells) and each dependent upon the properties of the relevant antigen molecules. In most cases the nature of the antigen may simply control the magnitude and/or duration of antigen receptor signaling. An antigen that by itself generates inefficient signaling may require additional signals from helper T cells to induce B-cell activation. In contrast, antigens derived from bacterial cell surface components, such as LPS, can directly activate B cells and macrophages. This vigorous, polyclonal responsiveness to certain bacterial components probably represents a specialized system to enhance antibody responses to bacteria, whereas helper T cell-dependent responses may be primarily useful in making antibodies against soluble proteins and viruses. Thus multiple pathways of B-cell activation probably are needed to generate adequate antibody responses against the variety of pathogenic micro-organisms encountered by vertebrates.