The anatomic features of the third cranial nerve (the oculomotor nerve) and the localization of lesions that affect it are reviewed. Recent considerations of the organization of the oculomotor fascicles in the ventral mesencephalon, the superior and inferior divisional palsies localized proximal to the cavernous sinus, and the possibility of the localization of ischemic oculomotor palsies to the mesencephalon rather than a peripheral site are emphasized. The characteristic manifestations of nuclear lesions (unilateral palsy of the third cranial nerve, weakness of the ipsilateral and contralateral superior rectus muscles, and bilateral incomplete ptosis) are described, as are other variations of nuclear involvement. Although proptosis is typically associated with orbital masses, it may also result from lesions of the cavernous sinus or (rarely) an intracranial lesion. Metastatic orbital tumors often are the first evidence of systemic spread in patients with cancer; infiltrative and mass lesions are the most common. Aberrant regeneration of the oculomotor nerve may occur months to years after the occurrence of an oculomotor lesion.