The σ2 receptor is an important target for the development of molecular probes in oncology because of its 10-fold higher density in proliferating tumor cells compared with that in quiescent tumor cells and because of the observation that σ2 receptor agonists are able to kill tumor cells via apoptotic and nonapoptotic mechanisms. Although recent evidence indicates that the σ2 receptor binding site is localized within the progesterone receptor membrane component 1 (PGRMC1), most information regarding this protein has been obtained using either radiolabeled or fluorescent receptor-based probes and from biochemical analysis of the effect of σ2 selective ligands on cells grown in culture. This article reviews the development of σ2 receptor ligands and presents an overview of how they have been used in vitro and in vivo to increase our understanding of the role of the σ2 receptor in cancer and proliferation.