The mammalian presenilin (PS) proteins mediate the posttranslational cleavage of several protein substrates, including amyloid precursor protein, Notch family members, and CD44, but they have also been suggested to function in diverse cellular processes, including calcium-dependent signaling and apoptosis. We carried out an integrative computational study of multiple genomic datasets, including RNA expression, protein interaction, and pathway analyses, which implicated PS proteins in Toll-like receptor signaling. To test these computational predictions, we analyzed mice carrying a conditional allele of PS1 and a germ line-inactivating allele of PS2, together with Cre site-specific recombinase expression under the influence of CD19 control sequences. Notably, B cells deficient in both PS1 and PS2 function have an unexpected and substantial deficit in both lipopolysaccharide and B cell antigen receptor-induced proliferation and signal transduction events, including a defect in anti-IgM-mediated calcium flux. Taken together, these results demonstrate a fundamental and unanticipated role for PS proteins in B cell function and emphasize the potency of (systems level) integrative analysis of whole-genome datasets in identifying novel biologic signal transduction relationships. Our findings also suggest that pharmacologic inhibition of PS for the treatment of conditions such as Alzheimer's disease may have potential consequences for immune system function.