Various cellular defense pathways are mobilized in response to stress that serve to limit potential damage to organelles and biochemical pathways that would disrupt normal cellular function or trigger cell death. Strategies utilized by cells subjected to various forms of stress include the activation of detoxification systems that act to eliminate the primary damaging molecules, remove damaged cellular macromolecules, or restore organelle and macromolecule function in cases where loss of activity is generated by reversible modifications or alterations in conformation (ie, misfolding). Central to many intracellular defense mechanisms that operate to limit damage to protein function are molecular chaperones of the heat shock protein (HSP) family. This review briefly discusses the molecular mechanisms that are thought to dictate the well-established neuroprotective effects of HSPs and highlight the recent attempts to use pharmacologic approaches to activate this important cellular defense pathway.