Sigma-1 receptors are molecular chaperones that may act as pathological mediators and targets for novel therapeutic applications in neurodegenerative diseases. Accumulating evidence indicates that sigma-1 ligands can either directly or indirectly modulate multiple neurodegenerative processes, including excitotoxicity, calcium dysregulation, mitochondrial and endoplasmic reticulum dysfunction, inflammation, and astrogliosis. In addition, sigma-1 ligands may act as disease-modifying agents in the treatment for central nervous system (CNS) diseases by promoting the activity of neurotrophic factors and neural plasticity. Here, we summarize their neuroprotective and neurorestorative effects in different animal models of acute brain injury and chronic neurodegenerative diseases, and highlight their potential role in mitigating disease. Notably, current data suggest that sigma-1 receptor dysfunction worsens disease progression, whereas enhancement amplifies pre-existing functional mechanisms of neuroprotection and/or restoration to slow disease progression. Collectively, the data support a model of the sigma-1 receptor as an amplifier of intracellular signaling, and suggest future clinical applications of sigma-1 ligands as part of multi-therapy approaches to treat neurodegenerative diseases.