Pseudo-allergic reactions may result from the activation of inflammatory or anaphylactic mechanisms independent of antigen-specific immune responses. Recent statistics show that pseudo-allergic reactions may represent as high as two thirds of all immediate hypersensitivity reactions, implying a great amount of morbidity and numerous health care costs. In this review, we concentrate on agents mediating pseudo-allergic reactions and evaluate accurately the available information on their modes of action. The agents discussed here are divided into three types:(i) Direct mast cell activators, which may activate mast cells in an IgE-independent manner, such as opioid drugs, basic secretagogues and calcium ionophore A23187;(ii) Complement activators, including liposomes, radiocontrast media and Cremophor EL, which may activate the complement system by different pathways: the classical pathway, the mannose-binding lectin pathway or the alternative pathway;(iii) Nonsteroidal anti-inflammatory drugs, which may inhibit the function of cyclooxygenase-1, resulting in the occurrence of adverse reactions. In addition, nonclinical detection methods of pseudoallergic reactions are also reviewed in order to supply valuable information for clinical diagnosis.