Author summary The human body is made from billions of cells comprizing many specialized cell types. All of these cells ultimately come from a single fertilized oocyte in a process that has two key features: proliferation, which expands cell numbers, and differentiation, which diversifies cell types. Here, we have examined the transition from proliferation to differentiation using B lymphocytes as an example. We find that the transition from proliferation to differentiation involves changes in the expression of genes, which can be categorized into cell-type–specific genes and broadly expressed “housekeeping” genes. The expression of many housekeeping genes is controlled by the gene regulatory factor Myc, whereas the expression of many B lymphocyte–specific genes is controlled by the Ikaros family of gene regulatory proteins. Myc is repressed by Ikaros, which means that changes in housekeeping and tissue-specific gene expression are coordinated during the transition from proliferation to differentiation.