Antiphospholipid syndrome (APS) is characterized by antiphospholipid antibodies (aPL) associated with thrombosis and/or pregnancy morbidity. However, there is a range of other manifestations associated with APS, called non-criteria manifestations that add significant morbidity to this syndrome and, some of them, represent difficult clinical situations to deal with. Other issues such as refractory treatment also represent challenging situations poorly addressed in the literature. Therefore, the purpose of this article is to review the management of difficult clinical situations in APS and provide information to help the readers in their decision-making process.