Antiphospholipid syndrome (APS) is an autoimmune thrombo-inflammatory disorder characterized by vascular thrombosis, pregnancy morbidity, and other manifestations driven by antiphospholipid autoantibodies. In this review, we present a clinical case that illustrates some diagnostic and therapeutic challenges in managing severe, relapsing APS manifestations, including microvascular injury and diffuse alveolar hemorrhage. We then discuss recent advances in our understanding of APS pathophysiology, emphasizing the critical role of anti-beta-2 glycoprotein I antibodies in triggering cell-specific inflammatory and thrombotic pathways. Finally, we speculate that achieving definitive disease control will require strategies that eliminate or effectively neutralize these pathogenic antibodies.