Activated B cells reacting to small amounts of CD40L (CD154) maintain homeostasis by suppressing default apoptosis. Additional outcomes, particularly differentiation, demand higher CD40 occupancy. Here, focusing on survival, we compared changes in the transcriptome of pleiotropically competent, early passage L3055 Burkitt's lymphoma cells confronted with low (picomolar) and high (nanomolar) concentrations of CD154 to gain insight into how a single receptor sets these distinct phenotypes. Of 267 genes altering transcriptional activity in response to strong CD154 tone, only 25 changed coordinately on low receptor occupancy. Seven of the top nine common up-regulated genes were targets of NF-kappaB. Direct measurement and functional inhibition of the NF-kappaB pathway revealed it to be central to a CD40-dependent survival signature. Although the canonical NF-kappaB axis was engaged by both signaling strengths equally, robust alternative pathway activation was a feature selective to a strong CD40 signal. Discriminatory exploitation of the two separate arms of NF-kappaB activation may indicate a principle whereby a cell senses and reacts differentially to shifting ligand availability. Identifying components selectively coupling CD40 to each axis could indicate targets for disruption in B cell pathologies underpinned by ectopic and/or hyper-CD154 activity such as neoplasia and some autoimmunities.