This review hopes to improve the selection of new tuberculosis (TB) vaccines by providing several perspectives on the immunization of humans, mice, guinea pigs, rabbits, and monkeys which have not usually been considered. (i) In human TB vaccine trials, the low rate of healing of Mycobacterium bovis BCG lesions (used as the control group) would distinguish individuals who might be helped by vaccination from the 95% who do not need it and would make these trials more conclusive. (ii) The rabbit immune response to Mycobacterium tuberculosis is much more effective in arresting tuberculosis than those of other laboratory animals, so pulmonary tubercle counting in rabbits should be included in all preclinical TB vaccine testing. (iii) Both delayed-type hypersensitivity (DTH) and cell-mediated immunity (CMI) are necessary to control the growth of M. tuberculosis. The testing of new TB vaccines in mice or in guinea pigs may not detect important antigens needed for human immunization. Mice respond poorly to tuberculin-like antigens that cause DTH. Guinea pigs respond poorly to antigens that cause CMI. Rabbits and humans respond well to both DTH and CMI antigens. Since monkeys are very susceptible to M. tuberculosis, they may not be as useful as rabbits for preclinical vaccine evaluation. (iv) Critical antigens (possibly ESAT-6 or CFP-10) might increase the immunity of the host to a greater extent than that produced by a natural M. tuberculosis infection and therefore would be useful in both prophylaxis and immunotherapy. Such critical antigens would increase the host's ability to neutralize key components of M. tuberculosis that enable it to survive in both laboratory animals and humans.