The MIST2 randomized trial addressed whether intrapleural fibrinolytic and enzymatic therapy could improve outcomes in pleural infection. Patients were randomized to tissue plasminogen activator, DNase, both agents or placebo. The combination of tPA plus DNase improved radiographic clearance of pleural collections, reduced the need for surgery and shortened hospital stay compared with placebo, whereas either agent alone did not show the same overall benefit. The study became a landmark because it provided evidence for a specific combination approach rather than simply supporting fibrinolysis as a class. For practicing pulmonologists, the result is most relevant when infected pleural fluid is incompletely resolving despite appropriate drainage and antibiotics and when escalation is being considered. This directly supports the NAPCON pleural track's emphasis on practical algorithms and deciding when to escalate. The study does not eliminate the need for early drainage or surgical consultation in appropriate patients. Instead, it provides an evidence-based adjunct for selected pleural infections and reinforces the value of coordinated respiratory, radiology and thoracic-surgery decision-making.