The sigma-1 (σ1) receptor, an enigmatic protein originally classified as an opioid receptor subtype, is now understood to possess unique structural and functional features of its own and play critical roles to widely impact signaling transduction by interacting with receptors, ion channels, lipids, and kinases. The σ1 receptor is implicated in modulating learning, memory, emotion, sensory systems, neuronal development, and cognition and accordingly is now an actively pursued drug target for various neurological and neuropsychiatric disorders. Evaluation of the five selective σ1 receptor drug candidates (pridopidine, ANAVEX2-73, SA4503, S1RA, and T-817MA) that have entered clinical trials has shown that reaching clinical approval remains an evasive and important goal. This review provides up-to-date information on the selective targeting of σ1 receptors, including their history, function, reported crystal structures, and roles in neurological diseases, as well as a useful collation of new chemical entities as σ1 selective orthosteric ligands or allosteric modulators.