The presence of antiphospholipid antibodies (aPL) in association with vascular thromboses (VT) and/or pregnancy morbidity (PM) is the hallmark of the Antiphospholipid Syndrome (APS). Increasingly, evidence indicates that PM in the APS involves direct targeting of endometrium and invading fetal trophoblast by aPL. Intravascular or intervillous blood clots are rarely found on histological examination of miscarriage samples from APS patients. In primary human trophoblast culture, aPL inhibit the expression of human chorionic gonadotrophin, induce apoptosis, decrease trophoblast fusion, alter expression of cell adhesion molecules, and limit trophoblast invasiveness. Maternal tissues may also be targeted by aPL since aPL have been shown to inhibit decidualization of cultured endometrial stromal cells and target the decidua when injected in pregnant mice, resulting in recruitment of neutrophils, complement activation, and a rapid increase in TNF-α levels. Thus the mechanism of pregnancy failure in APS is complex and involves local inflammation, impaired decidualisation, disruption of normal trophoblast function and cell death. In this article we review the evidence that different subsets of aPL directly target trophoblast and endometrial cells and the mechanisms that may be involved. The potential diagnostic and therapeutic implications of these findings will then be discussed.