Some monoclonal antibodies (mAbs) are able to induce platelet activation and/or aggregation in vitro. Such mAbs show specificity to important platelet membrane glycoproteins (GPs), including GPIIb/IIIa, GPIV, and the HLA complex. Different mechanisms are implicated in mAb-mediated platelet activation: mAbs can interact contemporarily with the target antigen by means of their Fab portion, and with the platelet Fc receptor (Fc gamma RII) through their Fc portion. Frequently, cross-linking Fc gamma RII causes receptor oligomerization, which in turn leads to platelet activation. On the other hand, it has been demonstrated that the target antigen may entirely transduce the activation signal. The activation event sometimes results from a conformational shift of the target antigen. Investigation of the mechanisms leading to mAb-mediated platelet activation will presumably increase our knowledge about platelet activation pathways, and will help in the management of patients having serum platelet-aggregating autoantibodies or alloantibodies.