The hippocampus plays a role in emotional regulation, spatial navigation, and formation of memories. Its complex network of connections supports key cognitive functions, like episodic memory and contextual processing. Its lesions may lead to a wide range of symptoms, most prominently epilepsy. These lesions include mesial temporal sclerosis, characterized by selective neuronal loss and gliosis, tumors, hamartomas, and aneurysms. To guarantee the best results, patients with mesial temporal sclerosis who are candidates for surgery need to undergo a comprehensive preoperative evaluation. Over the past century, numerous surgical techniques have been developed to securely access this extremely delicate area; each technique is tailored to the lesion’s location and associated safety concerns. These include transsylvian, transcortical, subtemporal, anterior temporal lobectomy, and recently described posterior methods. This chapter summarizes classic surgical approaches as well as recent innovations, such as minimally invasive interventions in the field.