Optical coherence tomography (OCT) is a nondestructive, high-resolution imaging modality, providing cross-sectional, architectural images at near histologic resolutions, with penetration depths up to a few millimeters. Optical frequency domain imaging is a second-generation OCT technology that has equally high resolution with significantly increased image acquisition speeds and allows for large area, high-resolution tissue assessments. These features make OCT and optical frequency domain imaging ideal imaging techniques for surface and endoscopic imaging, specifically when tissue is unsafe to obtain and/or suffers from biopsy sampling error. This review focuses on the clinical impact of OCT in coronary, esophageal, and pulmonary imaging and the role of the pathologist in interpreting high-resolution OCT images as a complement to standard tissue pathology.