The sigma-1 (σ₁) receptor has been associated with regulation of intracellular Ca²⁺ homeostasis, several cellular signaling pathways, and inter-organelle communication, in part through its chaperone activity. In vivo, agonists of the σ₁ receptor enhance brain plasticity, with particularly well-described impact on learning and memory. Under pathological conditions, σ₁ receptor agonists can induce cytoprotective responses. These protective responses comprise various complementary pathways that appear to be differentially engaged according to pathological mechanism. Recent studies have highlighted the efficacy of drugs that act through the σ₁ receptor to mitigate symptoms associated with neurodegenerative disorders with distinct mechanisms of pathogenesis. Here, we will review genetic and pharmacological evidence of σ₁ receptor engagement in learning and memory disorders, cognitive impairment, and neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and Huntington’s disease.