This review evaluates the available information on the effects of mainstream and environmental tobacco smoke on the immune system in animals and humans. The primary emphasis is on mainstream smoke since little information is available on the effects of environmental smoke. The effects of mainstream tobacco smoke on the immune system in humans and animals are similar. Animals exposed to mainstream tobacco smoke for periods of a few weeks generally exhibit a slight immunostimulation. However, subchronic and chronic exposure studies indicate that immunosuppressive changes develop. Lymphocyte proliferation in response to the mitogens PHA and LPS is decreased, suggesting compromise of cell function. Antibody production can be suppressed. Smoke-exposed animals that are challenged with metastasizing tumors or viruses have been shown to exhibit a higher incidence of tumorigenic and infectious diseases, respectively. Localized immunological changes in the lung can include reduction of bronchus-associated lymphoid tissue and immunoglobulin levels. Smoking-related changes in the peripheral immune system of humans have included elevated WBC counts, increased cytotoxic/suppressor and decreased inducer/helper T-cell numbers, slightly suppressed T-lymphocyte activity, significantly decreased natural killer cell activity, lowered circulating immunoglobin titers, except for IgE which is elevated, and increased susceptibility to infection. The effects of environmental tobacco smoke on the immune system, in contrast to mainstream tobacco smoke, have just begun to be investigated and information available in the literature, to date, is limited. Immunoreactive substances are known to be present in environmental tobacco smoke, but to date, environmental tobacco smoke has been more closely associated with irritation than sensitization. A few studies have indicated a potential for environmental smoke-induced hypersensitivity and suppression of immunoregulatory substances. In contrast, other investigators have failed to detect immunological or other biological changes associated with environmental smoke. Clearly, more research is needed to resolve these differences.