Chemical rescue of catalytically defective mutant enzymes has been a productive approach to studying enzyme function in vitro, but applications of the technique in vivo have so far met with limited success. Qiao et al. have achieved rapid and reversible rescue of the protein tyrosine kinase Src in live cells using the small molecule imidazole. The work provides insight into the mitogen-activated protein (MAP) kinase signaling pathway, including identifying several new Src substrates. Besides being a useful tool for studying cell signaling, small molecules that rescue disease-related mutant enzymes may have therapeutic potential.