B lymphocytes provide the cellular basis of the humoral immune response. All stages of this process, from B-cell activation to formation of germinal centers and differentiation into memory B cells or plasma cells, are influenced by extrinsic signals and controlled by transcriptional regulation. Compared to naïve B cells, memory B cells display a distinct expression profile, which allows for their rapid secondary responses. Indisputably, many B-cell malignancies result from aberrations in the circuitry controlling B-cell function, particularly during the germinal centre (GC) reaction. Here, we review new insights into memory B-cell subtypes, recent literature on transcription factors regulating human B-cell differentiation and further evidence for B-cell lymphomagenesis emanating from errors during GC cell reactions.