The hippocampus is one of the most sophisticated structures in the brain, owing to its complex anatomy, intriguing functions, relationship with other structures, and relevant associated symptoms. Despite being a structure analyzed for centuries, its anatomy and physiology in the human body are still being extensively studied, as well as associated pathologic conditions and potential biomarkers. It can be affected by a broad group of diseases that can be classified as congenital, degenerative, infectious or inflammatory, neoplastic, vascular, or toxic-metabolic disease. The authors present the anatomy and close structures, function, and development of the hippocampus, as well as an original algorithm for imaging diagnosis. The algorithm includes pathologic conditions that typically affect the hippocampus and groups them into nodular (space occupying) and nonnodular pathologic conditions, serving as a guide to narrow the differential diagnosis. MRI is the imaging modality of choice for evaluation of the hippocampus, and CT and nuclear medicine also improve the analysis. The MRI differential diagnosis depends on anatomic recognition and careful characterization of associated imaging findings such as volumetric changes, diffusion restriction, cystic appearance, hyperintensity at T1-weighted imaging, enhancement, or calcification, which play a central role in diagnosis along with clinical findings. Some pathologic conditions arising from surrounding structures such as the amygdala are also important to recognize. Pathologic conditions of the hippocampus can be a challenge to diagnose because they usually manifest as similar clinical syndromes, so the imaging findings play a potential role in guiding the final diagnosis. Online supplemental material is available for this article. ©RSNA, 2022.