The realization, that the immune system can be the target of many chemicals including environmental contaminants and drugs with potentially adverse effects on the host's health, has raised serious concerns within the public and the regulatory agencies. At present, assessment of immunotoxic effects relies on different animal models and several assays have been proposed to characterize immunosuppression and sensitization. The use of whole animals, however, presents many secondary issues, such as expense, ethical concerns, and eventual relevance to risk assessment for humans. Furthermore, due to the new policy on chemicals (REACH), in the European Union, in vitro methods will play a major role in the near future. In addition, there is still a lack of human cell-based immunotoxicity assays for predicting the toxicity of xenobiotics toward the immune system in a simple, fast, economical, and reliable way. Hypersensitivity and immunosuppression, for which animal models have been developed and validated, are considered the primary focus for developing in vitro methods in immunotoxicology. Nevertheless, in vitro assays, as well as in vivo models, to detect immunostimulation and autoimmunity are also needed. Even if no validated alternative in vitro tests to assess immunotoxicity exist, in the last decade, much progress has been made toward these assays. Such models can be, at least, used for the pre-screening and hazard identification of unintended immunosuppression and contact hypersensitivity of direct immunotoxicants. Following a brief introduction to immunotoxicology and to in vivo models use to assess immunotoxicity, this manuscript will review the state-of-the-art in the field of in vitro immunotoxicity.