Combining mathematical modeling with experiments enables quantitative understanding of cell signaling, transcriptional regulation, and cell fate decisions. Here, we provide a systems biology approach to link signal transduction with B cells fate decisions, to enable quantitative prediction of B-cell proliferation, and differentiation. We describe methodology to run simulations that reveal how signal transduction regulates gene expression and predicts cell fate decision. We describe how to quantitively validate modeling predic- tions with wet-lab experiments.