In the face of emerging infectious diseases caused by rapidly evolving and highly virulent pathogens, such as influenza, we are challenged to develop innovative vaccine strategies that can induce lasting protection. Since CD4 T cells are needed to generate and maintain protective B-cell and CD8 T-cell immunity, and can also mediate additional protective mechanisms, vaccines should ideally elicit efficient CD4 T cell, in addition to CD8 T and B-cell responses. We outline here the process of CD4 T-cell differentiation from naïve to effector and from effector to memory with an emphasis on how exposure to microbial products and variables in antigen presentation can impact the functional quality and heterogeneity of activation-based CD4 T-cell subsets in vitro and in vivo. We discuss the impact of different phases of antigen recognition, the inflammatory milieu, acute versus chronic antigen presentation, and the contribution of residual antigen depots on CD4 T-cell effector differentiation and the formation and maintenance of CD4 T-cell memory. We propose that novel vaccine strategies, which incorporate both microbial products and antigen targeting, may provide a flexible and long-lived memory CD4 T-cell pool.