Vaccines were originally developed to prevent or ameliorate infectious disease. As knowledge of immune function and appreciation of immunodeficiency has developed, researchers have used vaccine responses as a tool to characterize the phenotypes of patients exhibiting various syndromes. Thus it has become possible for a clinician to evaluate individual responses to vaccines to interrogate the immunocompetence of their patients. Although there have been many advances in these areas, we still have much to learn about the quantity and quality of humoral and cellular vaccine responses in healthy and immunodeficient subjects and how that knowledge can then be extrapolated to diagnostic purposes. Adverse effects of vaccines have been recognized for many years, especially the occurrence of infections caused by viable vaccine organisms in immunodeficient hosts. Nevertheless, vaccines are essential for disease prevention in immunodeficient patients, just as they are for healthy subjects. Clinicians must understand the appropriate and safe use of vaccines in patients with immunodeficiency. This review highlights some recent advances and ongoing challenges in application of vaccines for the diagnosis and treatment of immunodeficiencies.