The sigma (σ) receptor system consists of at least two major receptor subtypes: σ1 and σ2. Several potential therapeutic applications would benefit from structural knowledge of the σ2 receptor but gaining this knowledge has been hampered by the difficulties associated with its isolation and, thus, characterization. Here, a ligand based approach has been adopted using the program PHASE® and a group of 41 potent and structurally diverse σ2 ligands to develop several pharmacophore models for different families of σ2 ligands. These pharmacophores were analyzed to identify the different binding modes to the receptor and were combined together to construct a comprehensive pharmacophore that was used to develop a structural model for the σ2 binding pocket. A total of six binding modes were identified and could be classified as neutral or charged modes. The results presented here also indicate the significance of hydrophobic interactions to σ2 binding and the requirement of hydrogen bonding interactions to increase the affinity for this receptor subtype. This work adds breadth to our knowledge of this receptor’s binding site, and should contribute significantly to the development of novel selective σ2 ligands.