Copper(II)-diacetyl-bis(N(4)-methylthiosemicarbazone), Cu-ATSM, labeled with a positron emitting isotope of copper ((60)Cu, (61)Cu, (62)Cu or (64)Cu) has been shown, in vitro and in vivo, to be selective for hypoxic tissue. In silico studies have explored the mechanism of its hypoxia selectivity, and clinical studies with this agent have shown non-invasive imaging data that is predictive of a cancer patients' response to conventional therapy. This Perspective discusses the evolution of Cu-ATSM, how its selectivity can be improved upon, and where this metal-ligand platform could be taken in the future.