Although B lymphopoiesis is one of the best-defined paradigms in cell differentiation, our knowledge of the regulatory mechanisms underlying its earliest processes, in which hematopoietic stem cells (HSCs) enter the B lineage, is limited. However, recent methodological advances in sorting progenitor cells and monitoring their epigenetic features have increased our understanding of HSC activities. It is now known that even the highly enriched HSC fraction is heterogeneous in terms of lymphopoietic potential. While surface markers and reporter proteins provide information on the sequential differentiation of B-lineage progenitors, complex interactions between transcription factors have also been shown to play a major role in this process. Epigenetic regulation of histones, nucleosomes, and chromatin appears to play a crucial background role in this elaborate transcription network. In this review, we summarize recent findings on the physiological processes of early B-lineage differentiation, which provides a new paradigm for understanding the harmonious action of genetic and epigenetic mechanisms.