The rapid emergence of multidrug-resistant pathogens, especially Gram-negative bacteria and mycobacteria, represents one of the major medical challenges of the 21st century. The gradual loss of effective classical antibiotics for many bacterial pathogens, combined with an increasing population density and mobility, urgently calls for the development of novel treatments. Here, we discuss the potential of adjuvant immunotherapies to selectively stimulate protective immune responses as a treatment option for bacterial infections. In order to elicit appropriate immune responses and to avoid unwanted inflammatory tissue damage, it is essential to identify ligands and receptor pathways that specifically control protective responses at the site of infection. We summarize existing data and discuss suitable candidate targets for future immunotherapies of infectious diseases.