Complicated pleural effusions and empyema with loculation and failed drainage are common clinical problems. In adults, intrapleural fibrinolytic therapy (IPFT) is commonly used with variable results, and therapy remains empiric. Despite the intrapleural use of various plasminogen activators (PAs)—fibrinolysins—for about 60 years, there is no clear consensus about which agent is most effective. Emerging evidence demonstrates that intrapleural administration of PAs is subject to rapid inhibition by PA inhibitor-1 and that processing of fibrinolysins is significantly influenced by other factors, including the levels and quality of pleural fluid DNA. Current therapy for loculation that accompanies pleural infections also includes surgery, which is invasive and for which patient selection can be problematic. Most of the clinical literature published to date has used flat dosing of IPFT in all subjects, but little is known about how that strategy influences the processing of the administered fibrinolysin or how this influences outcomes. We developed a new test of pleural fluids ex vivo, which is called the fibrinolytic potential, in which a dose of a fibrinolysin is added to pleural fluids ex vivo after which the fibrinolytic activity is measured and normalized to baseline levels. Testing in preclinical and clinical empyema fluids reveals a wide range of responses, indicating that individual patients will likely respond differently to flat dosing of fibrinolysins. The test remains under development but is envisioned as a guide for dosing of these agents, representing a novel candidate approach to personalization of IPFT.