B cells of the immune system are a leading model for the analysis of gene regulatory networks (GRNs) and cell type specific transcriptional control mechanisms. They represent a featured mammalian cell state in the ENCODE project for in depth chromatin and transcription factor profiling. Furthermore, the loci encoding the antibody heavy and light chain genes (IgH and IgL) have been used to uncover novel mechanisms of somatic DNA recombination and hypermutation that enable the generation of highly diverse antibody repertoires and affinity maturation in response to pathogen encounters or vaccines. Importantly, variation in the human B cell regulatory genome has been associated with autoimmune diseases and vaccine responses. In spite of these impressive advances, there has not been a comprehensive attempt to delineate the cis-regulome of primary human B cells in their resting, activated and terminally differentiated states or to assemble a signaling induced gene regulatory network that controls the activation dynamics and differentiation of B cells. This has impeded efforts to systematically analyze the consequences of genomic variation on the structure and temporal dynamics of the underlying B cell regulatory network in human health and disease. Based on our success in assembling the first comprehensive cis-regulome for primary murine B cells by coupling structural and functional genomics, an inter-disciplinary team is proposing to address the two major challenges highlighted above for human B cells. Thus, we hope to advance a generalizable framework for analyzing the causal connections between human genome variation and dynamic gene network regulation in diverse biological contexts.