This review provides a critical and thorough overview of the radiopharmaceutical development and in vivo evaluation of all apoptosis-detecting radioligands that have emerged so far, along with their possible applications in nuclear medicine. The following SPECT and PET radioligands are discussed: all forms of halogenated Annexin V (i.e. (123)I-labelled, (124)I-labelled, (125)I-labelled, (18)F-labelled), (99m)Tc/(94m)Tc-labelled Annexin V derivatives using different chelators and co-ligands (i.e. BTAP, Hynic, iminothiolane, MAG(3), EDDA, EC, tricarbonyl, SDH) or direct (99m)Tc-labelling, (99m)Tc-labelled Annexin V mutants and (99m)Tc/(18)F-radiopeptide constructs (i.e. AFIM molecules), (111)In-DTPA-PEG-Annexin V, (11)C-Annexin V and (64)Cu-, (67)Ga- and (68)Ga-DOTA-Annexin V. In addition, the potential role and clinical relevance of anti-PS monoclonal antibodies and other alternative apoptosis markers are reviewed, including: anti-Annexin V monoclonal antibodies, radiolabelled caspase inhibitors and substrates and mitochondrial membrane permeability targeting radioligands. Nevertheless, major emphasis is placed on the group of Annexin V-based radioligands, in particular (99m)Tc-Hynic-Annexin V, since this molecule is by far the most extensively investigated and best-characterised apoptosis marker at present. Furthermore, the newly emerging imaging modalities for in vivo detection of programmed cell death, such as MRI, MRS, optical, bioluminescent and ultrasound imaging, are briefly described. Finally, some future perspectives are presented with the aim of promoting the development of potential new strategies in pursuit of the ideal cell death-detecting radioligand.