Methods of protecting cells against cytotoxic insults are provided. The methods involve administering a composition including a Toll-like receptor (TLR) ligand, for instance a TLR7, TLR8, or TLR9 ligand to a subject. The methods are applicable to the protection of neural and non-neural cells. For example, methods of protecting a neural cell against excitotoxic brain injury are provided. Methods for preparing medicaments for the prophylactic treatment of excitotoxic injury, ischemia and/or hypoxia are also provided. Also provided are compositions for use in the described methods.