Diagnosis and management of a systemic vasculitis are among the most demanding challenges in clinical medicine. A patient with a past history of cryptogenic organizing pneumonia presents with new bilateral lung lesions, unilateral pleural effusion, and significant proteinuria. The patient tested p-ANCA and anti-MPO positive but c-ANCA negative. A diagnosis of granulomatosis with polyangiitis GPA was reached after performing both renal and lung biopsies. Step-by-step differential diagnosis and management are discussed.