The successful establishment of humoral memory response depends on at least two layers of defense. Pre‐existing protective antibodies secreted by long‐lived plasma cells act as a first line of defense against reinfection (“constitutive humoral memory”). Previously, a second line of defense in which pathogen‐experienced memory B cells are rapidly reactivated to produce antibodies (“reactive humoral memory”), was considered as simply a back‐up system for the first line (particularly for re‐infection with homologous viruses). However, in the case of re‐infection with similar but different strains of viruses, or in response to viral escape mutants, the reactive humoral memory plays a crucial role. Here, we review recent progress in our understanding of how memory B cells are generated in the pre‐GC stage and during the GC reaction, and how these memory B cells are robustly reactivated with the help of memory Tfh cells to generate the secondary antibody response. In addition, we discuss how these advances may be relevant to the quest for a vaccine that can induce broadly reactive antibodies against influenza and HIV.