A lung biopsy is often required for a definitive diagnosis when pulmonary vasculitis or alveolar hemorrhage is suspected. It may be of great value in excluding important diagnostic considerations such as infections, neoplasms, sarcoidosis, and others. In patients with pulmonary-renal syndrome in whom there is a predominant renal involvement, renal biopsy is a preferable alternative since it is easier to perform and often times more diagnostic. Furthermore, the addition of cytotoxic therapy (eg, cyclophosphamide) without tissue confirmation of a reversible inflammatory vasculitis is controversial and potentially dangerous. Because the introduction of cyclophosphamide has dramatically affected the course and outcome of many of the small-vessel vasculitis syndromes, early diagnostic confirmation is of importance. We recommend an aggressive approach, including a biopsy from the predominantly involved organ that has the highest probability of yielding a definitive diagnosis. Clinical and radiographic characteristics such as age, sex, time course, systemic and pulmonary manifestations, and the pattern and extent of extrapulmonary involvement should be correlated with laboratory data such as p-ANCA or c-ANCA levels and histopathologic findings. These correlations are required to effectively manage these serious, yet potentially reversible, syndromes.