Systemic acquired resistance (SAR), initiated by a plant upon recognition of microbial effectors, involves generation of a mobile signal at the primary infection site, which translocates to and activates defense responses in distal tissues via unknown mechanism(s). We find that an acyl carrier protein, ACP4, is required to perceive the mobile SAR signal in distal tissues of Arabidopsis. Although acp4 plants generated the mobile signal, they failed to induce the systemic immunity response. Defective SAR in acp4 plants was not due to impairment in salicylic acid (SA)-, methyl SA-, or jasmonic acid-mediated plant hormone signaling pathways but was associated with the impaired cuticle of acp4 leaves. Other cuticle-impairing genetic mutations or physical removal of the cuticle also compromised SAR. This cuticular requirement was relevant only during mobile signal generation and its translocation to distal tissues. Collectively, these data suggest an active role for the plant cuticle in SAR-related molecular signaling.