The antiphospholipid syndrome (APS) is an autoimmune thrombophilic disorder that was described as a diagnostic entity over 30 years ago. And yet the pathogenic mechanisms that are responsible for its clinical manifestations remain to be definitively established. The syndrome is defined by (1) the concurrence of vascular thrombosis and/or pregnancy complications together with (2) positivity for immunoassays and coagulation tests that were derived from clinical observations of two anomalous laboratory test results—specifically, false positivity for syphilis infection in uninfected individuals and the finding of inhibitors of blood coagulation in patients who lacked any bleeding tendencies. Over the years, these were standardized into immunoassays and coagulation assays for APS. Here, we describe how prior knowledge of the immunologic and coagulation aspects of the disorder led to research involving a range of imaging modalities including light microscopy, immunohistochemistry, confocal scanning laser microscopy, transmission and scanning electron microscopy, and atomic force microscopy. In turn, the results from those studies led to a “reimagining” of APS that has advanced the understanding of pathogenic mechanisms of the disorder and has led to the development of novel mechanistically based diagnostics along with potential new treatment approaches that target disease mechanisms.