Differentiation of naïve B cells, including immunoglobulin class-switch DNA recombination, is critical for the immune response and depends on the extensive integration of signals from the B-cell receptor (BCR), tumor necrosis factor (TNF) family members, Toll-like receptors (TLRs), and cytokine receptors. TLRs and BCR synergize to induce class-switch DNA recombination in T cell-dependent and T cell-independent antibody responses to microbial pathogens. BCR triggering together with simultaneous endosomal TLR engagement leads to enhanced B-cell differentiation and antibody responses. Te requirement of both BCR and TLR engagement would ensure appropriate antigen-specific activation in an infection. Co-stimulation of TLRs and BCR likely plays a significant role in anti-microbial antibody responses to contain pathogen loads until the T cell-dependent antibody responses peak. Furthermore, the temporal sequence of different signals is also critical for optimal B cell responses, as exemplified by the activation of B cells by initial TLR engagement, leading to the up-regulation of co-stimulatory CD80 and MCH-II receptors, which result in more efficient interactions with T cells, thereby enhancing the germinal center reaction and antibody affinity maturation. Overall, BCR and TLR stimulation and the integration with signals from the pathogen or immune cells and their products determine the ensuing B-cell antibody response.