The antiphospholipid syndrome (APS) is characterized by a range of clinical features (primarily thrombosis and/or obstetric-related), together with the presence of antiphospholipid antibody (aPL) as detected by a diverse range of laboratory tests. APS remains a significant diagnostic and management challenge for clinicians across a wide range of specialties, some 30 years after APS was first described as a discrete clinical entity. This is due to ongoing issues regarding nomenclature, the diagnosis of APS in individual patients, the expanding range of recognized clinical manifestations and of APS-related laboratory tests, and management issues in particular APS patient subgroups (including obstetric and catastrophic APS). In addition to the presence of appropriate clinical features, the diagnosis of APS fundamentally requires the finding of positive aPL test result(s), which is hampered by ongoing problems with assay reproducibility and standardization. This review focuses on ongoing dilemmas and issues related to clinical and laboratory aspects of APS including: (1) diagnostic challenges posed by the protean clinical manifestations of APS; (2) current nomenclature and recent proposals for revision of the 2006 international classification criteria; (3) an overview of some key issues related to aPL testing; (4) potential pitfalls of applying the APS classification criteria as diagnostic criteria; and (5) the controversial subgroups of seronegative APS and non-APS aPL positivity.