CD4+ T cells orchestrate innate and adaptive immunity. In the central nervous system they modulate immune responses including cell trafficking and glial neuroregulatory functions through an array of soluble molecules cell-cell interactions affecting tissue homeostasis. During disease their roles evolve to an auto-aggressive or, alternatively, protective phenotype. How such a balance is struck in the setting of neurodegenerative disorders may reflect a dichotomy between regulatory T cell, anti-inflammatory and neuroprotective activities versus effector T cell inflammation and neurodegeneration. Interestingly, such roles may show commonalities amongst neurodegenerative diseases. Herein we focus on strategies to modulate such CD4+ T cell responses for therapeutic gain.