Background: Anatomic segmentectomy is a versatile sublobar resection approach that can be both diagnostic and therapeutic in the setting of the indeterminate pulmonary nodule (IPN), metastasectomy, as well as small, peripheral cancers. We analyzed the clinical indications and perioperative outcomes after anatomic segmentectomy and explored its utility in the diagnosis and treatment of IPNs and small stage IA lung cancers. Methods: This study is a retrospective review of 785 consecutive patients undergoing anatomic segmentectomy from 2002 to 2010. Primary outcome variables include perioperative course, morbidity, mortality, recurrence patterns, and survival. Results: Surgical indications included IPN (62.4%), known lung cancer (27.6%), suspected metastasis (4.1%), bullous disease (3.7%), or other (2.2%). Video-assisted thoracic surgery was employed in 468 (59.6%) and open thoracotomy in 317 (40.4%) patients. Median length of stay was 6 days. Overall complication rate was 34.9%. Thirty-day mortality was 1.1%. Among 490 patients with an IPN, 381 (77.7%) were found to have lung cancer, 41 (8.4%) metastatic cancer, and 68 (13.9%) benign disease. Among patients with pathologic stage IA lung cancer, there was no difference in recurrence rates (14.5% vs 13.9%) or 5-year freedom from recurrence estimates (78% in each group, p = 0.738) when comparing segmentectomy and lobectomy. Conclusions: Anatomic segmentectomy provides acceptable morbidity and mortality when approaching the IPN. Cancer is identified in 86% of lesions. Complete surgical resection can be achieved with generous parenchymal margins and thorough nodal staging for small, peripheral stage IA non-small cell lung cancer. The use of anatomic segmentectomy should be considered in this era of competing image-guided diagnostic and therapeutic approaches to peripheral lung pathology.