It is clear that the mammalian zona pellucida contains tissue-specific antigens that cross-react among certain species. Certain of these antigens generate antibodies that inhibit sperm attachment. Polyclonal antibody production may be an important aspect of this inhibition. In certain species there are other effects of anti-zona antibodies, such as direct action on the ovary. It is uncertain whether immunization with zona antigens will ever be a practical method of contraception in humans. Such vaccination might require unacceptable adjuvants or large amounts of antigen. The persistence and effectiveness of the antibody is not yet proven, and pregnancy has occurred in some despite presence of anti-zona autoantibodies. A safe and effective vaccine may still be found, however, given the large variety of zona pellucida antigens available. The cause of naturally occurring anti-zona pellucida antibodies in humans is unknown. The incidence of these antibodies depends on the assay used. The significance of positivity in a given individual is also uncertain. A number of patients will conceive if other concurrent fertility problems are treated. Positive results should be confirmed by a second method, preferably by testing the sera against human ova. Specific treatment by steroids or other immunosuppressive regimens remains controversial.