Salicylic acid (SA) is a critical hormone for signaling innate immunity in plants. Here we present the purification and characterization of SA-binding protein 2 (SABP2), a tobacco protein that is present in low abundance and specifically binds SA with high affinity. Sequence analysis predicted that SABP2 is a lipase belonging to the alpha/beta fold hydrolase super family. Confirming this prediction, recombinant SABP2 exhibited lipase activity against several synthetic substrates. Moreover, this lipase activity was stimulated by SA binding and may generate a lipid-derived signal. Silencing of SABP2 expression suppressed local resistance to tobacco mosaic virus, induction of pathogenesis-related 1 (PR-1) gene expression by SA, and development of systemic acquired resistance. Together, these results suggest that SABP2 is an SA receptor that is required for the plant immune response. We further propose that SABP2 belongs to a large class of ligand-stimulated hydrolases involved in stress hormone-mediated signal transduction.