Epilepsy is one of the most common neurological disorders. In most patients with epilepsy, seizures respond to available medications. However, a significant number of patients, especially in the setting of medically-intractable epilepsies, may experience different degrees of memory or cognitive impairment, behavioral abnormalities or psychiatric symptoms, which may limit their daily functioning. As a result, in many patients, epilepsy may resemble a neurodegenerative disease. Epileptic seizures and their potential impact on brain development, the progressive nature of epileptogenesis that may functionally alter brain regions involved in cognitive processing, neurodegenerative processes that relate to the underlying etiology, comorbid conditions or epigenetic factors, such as stress, medications, social factors, may all contribute to the progressive nature of epilepsy. Clinical and experimental studies have addressed the pathogenetic mechanisms underlying epileptogenesis and neurodegeneration. We will primarily focus on the findings derived from studies on one of the most common causes of focal onset epilepsy, the temporal lobe epilepsy, which indicate that both processes are progressive and utilize common or interacting pathways. In this chapter we will discuss some of these studies, the potential candidate targets for neuroprotective therapies as well as the attempts to identify early biomarkers of progression and epileptogenesis, so as to implement therapies with early-onset disease-modifying effects.