Adaptive humoral immunity to extracellular bacteria is largely mediated by antibody specific for both protein and polysaccharide antigens. Proteins and polysaccharides are biochemically distinct, and as a result are processed differently by the immune system, leading to different mechanistic pathways for eventual elicitation of specific Ig isotypes. Much of our current knowledge concerning the parameters underlying anti-protein and anti-polysaccharide Ig responses have come from studies using soluble, purified antigens. However, the lessons learned from these studies are not entirely applicable to the mechanisms underlying physiologic anti-protein and anti-polysaccharide Ig responses to intact bacteria. Specifically, unlike isolated, soluble antigens, intact bacteria are complex particulate immunogens in which multiple protein and polysaccharide antigens, and bacterial adjuvants (e.g. Toll-like receptor ligands) are co-expressed, indeed often physically linked. In this review, data from a series of recent studies are discussed in which heat-killed, intact Streptococcus pneumoniae was used as an immunogen to study the mechanisms underlying in vivo anti-protein and antipolysaccharide Ig isotype induction. An unexpected role for CD4+ T cells and dendritic cells for induction of IgG antipolysaccharide responses by intact bacteria is discussed, and shown to have distinct mechanistic features from those that mediate anti-protein responses. The further role of cytokines, Toll-like receptors, and B cell receptor signaling in mediating these responses, and its implications for the effectiveness of anti-pneumococcal, polysaccharide-based vaccines, is also discussed.