CD4+ T cells effect protective immunity against many clinically important intracellular bacterial pathogens by recognising and responding to pathogen-derived peptide antigens. Salmonella enterica serovar Typhimurium, a well-established model for probing CD4+ T cell immunity, has a proteome of >4,500 ORFs with >1,000 proteins expressed in the host, yet only a small subset of such protein antigens appear to elicit high-quality, protective CD4+ T cell responses in a phenomenon known as immunodominance. The identity of these immunodominant antigens, and the mechanisms that govern their selection, remain largely unknown to date. We have recently developed a global and unbiased approach for identifying Salmonella-derived peptide antigens that are naturally presented by MHC-II molecules for activating CD4+ T cells. While we found CD4+ T cells against many of these peptide antigens in an infected host, the majority of infection-induced CD4+ T cells are focused on just a small subset of these newly identified antigens. Interestingly, we observed that different antigens induced distinct types of cytokine responses in the host, suggesting a direct role for antigens in shaping the responses from, and the microenvironment of, activated CD4+ T cells. These observations have enabled the discussion of some key questions, such as whether there are identifiable commonalities between immunodominant CD4+ T cell antigens, or whether antigen identity confers differential effector/memory CD4+ T cell development. The ultimate goal is to provide a paradigm for antigen selection mechanisms that is broadly applicable to CD4+ T cell-mediated immunity against Salmonella and other complex pathogens.