Plastid-derived signals are known to coordinate expression of nuclear genes encoding plastid-localized proteins in a process termed retrograde signaling. To date, the identity of retrograde-signaling molecules has remained elusive. Here, we show that methylerythritol cyclodiphosphate (MEcPP), a precursor of isoprenoids produced by the plastidial methylerythritol phosphate (MEP) pathway, elicits the expression of selected stress-responsive nuclear-encoded plastidial proteins. Genetic and pharmacological manipulations of the individual MEP pathway metabolite levels demonstrate the high specificity of MEcPP as an inducer of these targeted stress-responsive genes. We further demonstrate that abiotic stresses elevate MEcPP levels, eliciting the expression of the aforementioned genes. We propose that the MEP pathway, in addition to producing isoprenoids, functions as a stress sensor and a coordinator of expression of targeted stress-responsive nuclear genes via modulation of the levels of MEcPP, a specific and critical retrograde-signaling metabolite. Display omitted ► The MEP pathway produces plastidial isoprenoids and serves as a plant stress sensor ► Excess light or wounding elevates the levels of isoprenoids intermediate, MEcPP ► Accumulation of MEcPP induces expression of selected stress genes in the nucleus ► MEcPP is a retrograde-signaling metabolite coordinating stress-response pathways A metabolite produced in plastids in response to stress in turn activates stress-response genes in the nucleus, providing insight into the signaling mechanisms that link plastids and nuclei.