Hippocampal Sclerosis (HS) is the most common underlying cause of Mesial Temporal Lobe Epilepsy (MTLE), and it's often the reason why many patients don't respond to medication. It involves the loss of specific neurons, an increase in glial cells, and a reshaping of the connections within the hippocampus. Even though there are many Antiepileptic Drugs (AEDs) available, a large number of MTLE-HS patients don't find relief with these medications and often need surgery. This resistance to drugs arises from the combination of structural damage in the hippocampus and intricate molecular processes, such as the increased activity ofdrug transporters that pump drugs out of cells, and ongoing inflammation in the brain. This review brings together the latest findings on the different anatomical and histopathologicaltypes of HS, what we can see using advanced brain imaging, the underlying molecular mechanisms, the cognitive and clinical consequences, and how it significantly affects drug resistance. Additionally, we will explore factors that help predict whether surgery or medication will be moreeffective, and we'll discuss future directions, emphasizing the importance of personalized treatment plans to improve patient results.