The sigma-2 (σ2) receptor is proving to be an important protein in the field of cancer biology. The observations that σ2 receptors have a 10-fold higher density in proliferating tumor cells than in quiescent tumor cells, and that σ2 receptor agonists are capable of killing tumor cells via apoptotic and non-apoptotic mechanisms, indicate that this receptor is an important molecular target for the development of radiotracers for imaging tumors using techniques such as Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) and for the development of cancer chemotherapeutic agents. In spite of recent promising results towards achieving these goals, research in this field has been hampered by the fact that the molecular identity of the protein sequence of the σ2 receptor is currently not known. Consequently, most of what is known about this protein has been obtained using either radiolabeled or fluorescent probes for this receptor, or biochemical analysis of the effect of σ2 selective ligands on cells growing under tissue culture conditions. This article provides a review of the development and use of σ2 receptor ligands, and how these ligands have been used with a variety of in vitro and in vivo models to gain a greater understanding of the role this receptor plays in cancer.