To assess the activity of deoxycytidine kinase (dCK), a drug-resistance-determining enzyme, we developed a new CEST MRI approach, in which the natural substrate, deoxycytidine (dC), is directly used as a CEST MRI reporter. Both in vitro and in vivo results showed that, upon the incubation or injection of dC, dCK(+) tumor cells have significantly higher CEST contrast at 2 ppm than dCK(-) cells, attributed to the accumulation of phosphorylated dC by dCK activity. Because dC is a clinically available agent, this ‘natural” MR molecular imaging method has great potential to be quickly translated to the clinic for patient stratification.