The hunt for novel tools to investigate empirical questions is ever present in psychophysiological research. Antibody response to vaccination has received increasing attention over recent years as a useful measure of in vivo immune function. There is now considerable evidence that the magnitude of the antibody response to vaccination is associated with a wide range of psychosocial factors. Further, there are preliminary indications that manipulating psychosocial variables, using both chronic and acute interventions, can also alter the efficacy of the vaccination. This review will discuss the theoretical and clinical relevance of the vaccine model in this context, and will address key methodological considerations for researchers considering adopting this approach. The review will also address how the strategic use of this model could help researchers further elucidate some of the remaining theoretical issues.