How, why, and when specific T and B lymphocytes respond against infection follow explicit rules, but how this can be assessed experimentally depends crucially on the methodology used. In this Viewpoint, we discuss the parameters of receptor specificity and antigen that determine whether an immune response can be accurately measured against model antigens and how this relates to protection against a given pathogen. We suggest that antigen structure, localization, dose, and time during which antigen is available are all decisive factors in regulating an immune response.