The design, synthesis, and evaluation of the Copper-Gad (CG) family, a new class of copper-activated magnetic resonance imaging (MRI) contrast agents, are presented. These indicators comprise a Gd3+-DO3A core coupled to various thioether-rich receptors for copper-induced relaxivity switching. In the absence of copper ions, inner-sphere water binding to the Gd3+ chelate is restricted, resulting in low longitudinal relaxivity values (r(1) = 1.2-2.2 mM(-1) s(-1) measured at 60 MHz). Addition of Cu+ to CG2, CG3, CG4, and CG5 and either Cu+ or Cu2+ to CG6 triggers marked enhancements in relaxivity (r(1) = 2.3-6.9 mM(-1) s(-1)). CG2 and CG3 exhibit the greatest turn-on responses, going from r(1) = 1.5 mM(-1) s(-1) in the absence of Cu+ to r(1) = 6.9 mM(-1) s(-1) upon Cu+ binding (a 360% increase). The CG sensors are highly selective for Cu+ and/or Cu2+ over competing metal ions at cellular concentrations, including Zn2+ at 10-fold higher concentrations. O-17 NMR dysprosium-induced shift and nuclear magnetic relaxation dispersion measurements support a mechanism in which copper-induced changes in the coordination environment of the Gd3+ core result in increases in q and r(1). T-1-weighted phantom images establish that the CG sensors re capable of visualizing changes in copper levels by MRI at clinical field strengths.