Our bodies are continuously exposed to various types of infectious pathogens. Vaccinations are the most cost effective way to protect our bodies against a variety of infectious microbes. The efficacy of most vaccines relies on protective antibody production and generation of memory B cells. These two key components develop mostly from B cells that participate in germinal center reactions. Recent efforts have highlighted the critical role of follicular helper CD4 T (Tfh) cells in the generation of germinal centers. Given that Bcl6 is a major transcription factor for Tfh differentiation, here we review recent developments in the understanding of signaling molecules that regulate Bcl6 expression in CD4 T cells, as a potential target for development of more efficacious vaccines.